TW202003525A - New heterocyclic compounds - Google Patents

Abstract

The invention provides new heterocyclic compounds having the general formula (Ic) (Ic) wherein A, L, X, m, n and R20 to R23 are as described herein, compositions including the compounds, processes of manufacturing the compounds and methods of using the compounds.

Description

Novel heterocyclic compounds

The present invention relates to organic compounds that can be used in the therapy or prevention of mammals, and in particular, to monoglyceride glycerolase (MAGL) inhibitors used in the treatment or prevention of the following disorders in mammals: nerve inflammation, nerve degeneration Sexual diseases, pain, cancer, mental disorders, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity , Stroke, epilepsy, anxiety, migraine and/or depression.

Endocannabinoids (EC) are signaling lipids that exert their biological effects by interacting with cannabinoid receptors (CBR) CB1 and CB2. It regulates a variety of physiological processes, including nerve inflammation, nerve degeneration, and tissue regeneration (Iannotti, FA et al., Progress in lipid research 2016 , 62 , 107-28.). In the brain, the main endogenous cannabinoid, 2-arachidene glycerol (2-AG), is produced by diacylglycerol lipase (DAGL) and hydrolyzed by the monoacylglycerol lipase MAGL. MAGL hydrolyzes 85% of 2-AG; the remaining 15% is hydrolyzed by ABHD6 and ABDH12 (Nomura, DK et al., Science 2011 , 334 , 809.). MAGL is expressed throughout the brain and most brain cell types, including neurons, astrocytes, oligodendrocytes, and microglia (Chanda, PK et al., Molecular pharmacology 2010 , 78 , 996; Viader, A. et al. , Cell reports 2015 , 12 , 798.). 2-AG hydrolysis results in the formation of arachidic acid (AA), which is a precursor of prostaglandins (PG) and leukotrienes (LT). In inflamed tissues, the oxidative metabolism of AA increases. Two main enzyme pathways involved in the oxidation of peanut oleic acid are involved in the inflammation process, namely cyclooxygenase that produces PG and 5-lipoxygenase that produces LT. Among the various cyclooxygenase products formed during inflammation, PGE2 is one of the most important products. These products have been detected at the site of inflammation, such as in the cerebrospinal fluid of patients with neurodegenerative disorders, and are believed to contribute to the inflammatory response and disease progression. MGL-deficient mice (Mgll-/-) exhibited significantly reduced 2-AG hydrolase activity and increased 2-AG content in the nervous system, while other phospholipids and neutral lipid substances containing arachidene acetyl groups ( Including cannabinoids (AEA) and other free fatty acids were unchanged. In contrast, the levels of AA and AA-derived prostaglandins and other arachidic acids (including prostaglandins E2 (PGE2), D2 (PGD2), F2 (PGF2), and prothrombin B2 (TXB2)) were strongly reduced. Phospholipase A ₂ (PLA ₂ ) is regarded as the main source of AA, but the content of AA in the brain of cPLA ₂ deficient mice has not changed, which strengthens the key role of MAGL in the brain to produce AA and regulate the process of brain inflammation .

Neuroinflammation is a common pathological feature of brain diseases, including (but not limited to) neurodegenerative diseases (such as multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, trauma Brain damage, neurotoxicity, stroke, epilepsy, and mental disorders such as anxiety and migraine). In the brain, the production of eicosanoids and prostaglandins controls the process of nerve inflammation. The pro-inflammatory agent lipopolysaccharide (LPS) caused a strong time-dependent increase in brain arachidic acid, which increase was significantly attenuated in Mgll-/- mice. LPS treatment also induces a widespread increase in proinflammatory cytokines (including interleukin-1-a (IL-1-a), IL-1b, IL-6 and tumor necrosis factor-a (TNF-a)), This increase is prevented in Mgll-/- mice.

Neuroinflammation is characterized by the activation of innate immune cells of the central nervous system, microglia and astrocytes. It is reported that anti-inflammatory drugs can inhibit the activation of glial cells and the progression of diseases including Alzheimer's disease and multiple sclerosis in preclinical models (Lleo A., Cell Mol Life Sci. 2007 , 64 , 1403 .). Importantly, the genetic and/or pharmacological disruption of MAGL activity also blocks LPS-induced activation of microglia in the brain (Nomura, DK et al., Science 2011 , 334 , 809.).

In addition, genetic and/or pharmacological disruption of MAGL activity has been shown to be protective in several animal models of neurodegeneration, including (but not limited to) Alzheimer's disease, Parkinson's disease, and multiple sclerosis. For example, irreversible MAGL inhibitors have been widely used in preclinical models of neuroinflammation and neurodegeneration (Long, JZ et al., Nature chemical biology 2009 , 5 , 37.). Systemic injection of this inhibitor recapitulates the phenotype of Mgll-/- mice in the brain, including increased 2-AG content, reduced AA content and related arachidic acid production, as well as preventing the production of cytokines and small cells after LPS-induced neuroinflammation Glial activation (Nomura, DK et al., Science 2011 , 334 , 809.), which as a whole confirmed that MAGL is a pharmaceutically acceptable target.

After genetic and/or pharmacological disruption of MAGL activity, the endogenous content of MAGL natural substrate 2-AG in the brain increases. It has been reported that 2-AG shows a beneficial effect on pain, such as an anti-nociceptive effect in mice (Ignatowska-Jankowska B. et al., J. Pharmacol. Exp. Ther. 2015 , 353 , 424.), and shows Beneficial effects on mental disorders (eg depression in chronic stress models) (Zhong P. et al., Neuropsychopharmacology 2014 , 39 , 1763.).

In addition, oligodendrocytes (OL) (ie, myelinating cells of the central nervous system) and their precursors (OPC) express cannabinoid receptor 2 (CB2) on their membranes. 2-AG is an endogenous ligand for CB1 and CB2 receptors. It is reported that both cannabinoids and pharmacological inhibition of MAGL both attenuate the susceptibility of OL and OPC to excitotoxic damage, and therefore may be neuroprotective (Bernal-Chico, A. et al., Glia 2015 , 63 , 163.). In addition, the pharmacological inhibition of MAGL increases the number of myelinating OL in the mouse brain, indicating that MAGL inhibition can promote the differentiation of OPC in myelinating OL in vivo (Alpar, A. et al., Nature communications 2014 , 5 , 4421 .). It has also been shown that inhibition of MAGL promotes myelination and functional recovery in a mouse model of progressive multiple sclerosis (Feliu A. et al., Journal of Neuroscience 2017 , 37 (35), 8385.).

Finally, in recent years, it is believed that metabolism, especially lipid metabolism, is of high importance in cancer research. Researchers believe that de novo fatty acid synthesis plays an important role in tumor development. Many studies have shown that endocannabinoids have anti-tumorigenic effects, including anti-proliferation, apoptosis induction and anti-metastatic effects. MAGL is an important enzyme for both lipid metabolism and endocannabinoid systems, and it is also a part of the gene expression imprint, contributing to different aspects of tumorigenesis (Qin, H. et al., Cell Biochem. Biophys . 2014 , 70 , 33; Nomura DK et al., Cell 2009 , 140 (1), 49-61; Nomura DK et al., Chem. Biol. 2011 , 18 (7), 846-856).

In conclusion, the inhibition and/or activation of MAGL is a promising novel therapeutic strategy for the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer and mental disorders. In addition, inhibiting the action and/or activation of MAGL is a promising novel therapeutic strategy for providing neuroprotection and remyelination. Therefore, the industry has a highly unmet medical need for novel MAGL inhibitors.

其中A、L、X、m、n及R²⁰ 至R²³ 係如本文所定義。In a first aspect, the present invention provides compounds of formula (Ic)

Wherein A, L, X, m, n and R ²⁰ to R ²³ are as defined herein.

與雜環胺2a 在鹼及脲形成試劑存在下反應，其中A、L、X、m、n及R²⁰ 至R²³ 係如本文所定義

以形成該等式(Ic)化合物。In another aspect, the present invention provides a process for making a compound of formula (Ic) as set forth herein, which comprises: using 4a, 5, 6, 7, 8, 8a-hexahydro-4H-pyrido[4, 3-b][1,4]oxazin-3-one ( 1 )

Reaction with heterocyclic amine 2a in the presence of a base and a urea-forming reagent, where A, L, X, m, n and R ²⁰ to R ²³ are as defined herein

To form the compound of formula (Ic).

In another aspect, the present invention provides compounds of formula (Ic) as set forth herein, which are manufactured according to the processes set forth herein.

In another aspect, the present invention provides compounds of formula (Ic) as set forth herein for use as therapeutically active substances.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (Ic) as described herein and a therapeutically inert carrier.

In another aspect, the present invention provides the use of a compound of formula (Ic) as set forth herein for inhibiting monoacylglycerol lipase (MAGL) in mammals.

In another aspect, the present invention provides the use of a compound of formula (Ic) as set forth herein for the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer and/or mental disorders in mammals.

In another aspect, the present invention provides the use of a compound of formula (Ic) as described herein for the treatment or prevention of multiple sclerosis, Alzheimer's disease, Parkinson's disease, muscle atrophy in mammals Lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, hepatocellular carcinoma, colon cancer development, ovarian cancer, neuropathic pain, neuropathy induced by chemotherapy, Acute pain, chronic pain and/or spasm associated with pain.

In another aspect, the present invention provides a compound of formula (Ic) as set forth herein, for use in a method of inhibiting monoacylglycerol lipase in a mammal.

In another aspect, the present invention provides compounds of formula (Ic) as described herein for use in the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, and/or mental disorders in mammals.

In another aspect, the present invention provides a compound of formula (Ic) as described herein for use in the treatment or prevention of multiple sclerosis, Alzheimer's disease, Parkinson's disease, muscle atrophy in mammals Lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, hepatocellular carcinoma, colon cancer development, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, acute Pain, chronic pain and/or spasm associated with pain.

In another aspect, the present invention provides the use of a compound of formula (Ic) as set forth herein for the preparation of a medicament for inhibiting monoacylglycerol lipase in mammals.

In another aspect, the invention provides the use of a compound of formula (Ic) as set forth herein for the preparation or treatment of mammalian neuroinflammation, neurodegenerative diseases, pain, cancer and/or mental Elixir of obstacles.

In another aspect, the present invention provides the use of a compound of formula (Ic) as described herein for the preparation of a medicament for the treatment or prevention of the following conditions in mammals: multiple sclerosis, Alzheimer's disease , Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, hepatocellular carcinoma, colon cancer, ovarian cancer, neuropathic pain 1. Neuropathy induced by chemotherapy, acute pain, chronic pain and/or spasm associated with pain.

In another aspect, the present invention provides a method for inhibiting monoacylglycerol lipase in a mammal, the method comprising administering to the mammal an effective amount of a compound of formula (Ic) as described herein.

In another aspect, the invention provides a method for treating or preventing neuroinflammation, neurodegenerative diseases, pain, cancer, and/or mental disorders in a mammal, the method comprising administering to the mammal an effective amount such as The compounds of formula (Ic) described herein.

In another aspect, the present invention provides for the treatment or prevention of multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity in mammals , Stroke, epilepsy, anxiety, migraine, depression, hepatocellular carcinoma, colon cancer, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, acute pain, chronic pain and/or pain-related spasm A method comprising administering to the mammal an effective amount of a compound of formula (Ic) as set forth herein.

DEFINITIONS Features, integers, characteristics, compounds, chemical moieties or groups described in connection with specific aspects, embodiments or examples of the present invention should be understood to apply to any other aspect, embodiment or example described herein unless incompatible. All features disclosed in this specification (including any accompanying patent application scope, abstract, and drawings) and/or all steps of any method or process so disclosed can be combined in any combination, but these features and/or At least some mutually exclusive combinations of steps are excluded. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel feature or any novel combination of features disclosed in this specification (including any accompanying patent application scope, abstract and drawings), or to any novel step of any method or process step disclosed as such or Any novel combination.

The term "alkyl" refers to a monovalent or multivalent (eg, monovalent or divalent) linear or branched saturated hydrocarbon group having 1 to 12 carbon atoms. In some preferred embodiments, the alkyl group contains 1 to 6 carbon atoms, such as 1, 2, 3, 4, 5, or 6 carbon atoms. In other embodiments, the alkyl group contains 1 to 3 carbon atoms, such as 1, 2, or 3 carbon atoms. Some non-limiting examples of alkyl groups include methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, isobutyl, second butyl, third butyl, and 2,2- Dimethylpropyl. A particularly preferred but non-limiting example of alkyl is methyl. The alkyl group may be substituted. Therefore, the term "substituted alkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is replaced by a substituent as described herein, preferably by a substituent selected from the group consisting of: halogen, hydroxy, alkoxy Group, arylalkoxy group, trialkylsilyloxy group, substituted or unsubstituted cycloalkyl group and substituted or unsubstituted heterocyclic group. Most preferably, "substituted alkyl" refers to an alkyl group in which one, two, or three hydrogen atoms of the alkyl group are replaced with a substituent selected from the group consisting of halogen, hydroxyl, alkoxy, and arylalkyl Oxygen, trialkylsilyloxy, substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocyclyl. Specific but non-limiting examples of substituted alkyl groups are 2-hydroxyethyl, 2-methoxyethyl, hydroxymethyl, methoxymethyl, trifluoromethyl, oxetan-3-yl -Methyl, (1-third butoxycarbonylazetidin-3-yl)methyl, cyclopropylmethyl, 1-(chloromethyl)-2-hydroxy-ethyl, 2-[第Tributyl(dimethyl)silyl]oxyethyl and benzyloxymethyl.

The term "alkoxy" refers to an alkyl group as previously defined, which is connected to the parent molecular moiety via an oxygen atom. Unless otherwise specified, alkoxy groups contain 1 to 12 carbon atoms. In some preferred embodiments, the alkoxy group contains 1 to 6 carbon atoms. In other embodiments, the alkoxy group contains 1 to 4 carbon atoms. In other embodiments, the alkoxy group contains 1 to 3 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and third butoxy. A particularly preferred but non-limiting example of alkoxy is methoxy.

The term "halogen" or "halo" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). Preferably, the term "halogen" or "halo" refers to fluorine (F), chlorine (Cl) or bromine (Br). Particularly preferred but non-limiting examples of "halogen" or "halo" are fluorine (F) and chlorine (Cl).

The term "cycloalkyl" as used herein refers to a saturated or partially unsaturated monocyclic or bicyclic hydrocarbon group having 3 to 10 ring carbon atoms. In some preferred embodiments, the cycloalkyl group is a saturated monocyclic hydrocarbon group having 3 to 8 ring carbon atoms. "Bicyclic cycloalkyl" means a cycloalkyl moiety consisting of two saturated carbocycles with two common carbon atoms, ie the bridge separating the two rings is a single bond or a chain of one or two ring atoms, and Refers to a spiro ring portion, that is, two rings are connected via a common ring atom. Preferably, the cycloalkyl group is a saturated monocyclic hydrocarbon group having 3 to 6 ring carbon atoms (for example, 3, 4, 5, or 6 carbon atoms). Some non-limiting examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

The term "cycloalkyloxy" refers to the group cycloalkyl-O-, ie, cycloalkyl substituted with an oxy group and connected to the parent molecular moiety through the oxy group.

The term "heterocyclic group" as used herein refers to a saturated or partially unsaturated monocyclic or bicyclic, preferably monocyclic system having 3 to 10 ring atoms, preferably 3 to 8 ring atoms, One, two or three of these ring atoms are heteroatoms selected from N, O and S, and the remaining ring atoms are carbon. Preferably, one to two of the ring atoms are selected from N and O, and the remaining ring atoms are carbon. "Bicyclic heterocyclyl" refers to a heterocyclic moiety consisting of two rings with two common ring atoms, that is, the bridge separating the two rings is a single bond or a chain of one or two ring atoms, and refers to spiro The ring part, that is, the two rings are connected via a common ring atom. Some non-limiting examples of monocyclic heterocyclic groups include azetidin-3-yl, azetidin-2-yl, oxetan-3-yl, oxetan-2-yl, 2- Pyroxyl pyridin-1-yl, 2-oxo pyrrolidin-3-yl, 5-oxo pyrrolidine-2-yl, 5-oxo pyrrolidine-3-yl, 2-oxo Yl-1-hexahydropyridyl, 2-oxo-3-hexahydropyridyl, 2-oxo-4-hexahydropyridyl, 6-oxo-2-hexahydropyridyl, 6- Pendant-3-hexahydropyridyl, 1-hexahydropyridyl, 2-hexahydropyridyl, 3-hexahydropyridyl, 4-hexahydropyridyl, morpholinyl, morpholin-2-yl and Morpholin-3-yl. The heterocyclic group may be substituted. Therefore, the term "substituted heterocyclic group" refers to a heterocyclic group in which at least one hydrogen atom of the heterocyclic group is replaced by a substituent as described herein, preferably by a substituent selected from the group consisting of: Unsubstituted alkyl, halogen and alkoxy, wherein the substituted alkyl is substituted with 1 to 3 substituents selected from the group consisting of hydroxy, halogen, alkoxy, arylalkoxy and cycloalkyl . Most preferably, "substituted heterocyclic group" refers to a heterocyclic group in which 1 to 2 hydrogen atoms of the heterocyclic group are replaced by a substituent selected from the group consisting of substituted or unsubstituted alkyl, halogen, and Alkoxy, wherein the substituted alkyl is substituted with 1 to 3 substituents selected from the group consisting of hydroxy, halogen, alkoxy, arylalkoxy and cycloalkyl. Specific but non-limiting examples of substituted heterocyclic groups are 2-methyl-5-oxo-pyrrolidin-1-yl, 4,4-difluoro-1-hexahydropyridyl, 1-third Butoxycarbonyl azetidin-3-yl and 1-third butoxycarbonyl azetidin-2-yl.

The term "heterocyclyloxy" refers to the group heterocyclyl-O-, that is, a heterocyclic group substituted with an oxy group and connected to the parent molecular moiety through the oxy group. Non-limiting examples of heterocyclyloxy are oxetanyloxy, such as oxetan-3-yloxy.

The term "aryl" refers to a monocyclic, bicyclic or tricyclic carbocyclic ring system having a total of 6 to 14 ring members, preferably 6 to 12 ring members and more preferably 6 to 10 ring members, and At least one ring in this system is aromatic. Some non-limiting examples of aryl groups include phenyl and 9H-茀yl (eg, 9H-茀-9-yl). A particularly preferred but non-limiting example of aryl is phenyl. The aryl group may be substituted. Therefore, the term "substituted aryl" refers to an aryl group in which at least one hydrogen atom of an aryl group is replaced by a substituent as described herein, for example, by a substituent selected from the group consisting of: halogen, cyano, alkoxy , Halogenated alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkyloxy Group, substituted or unsubstituted cycloalkyloxyalkyl, substituted or unsubstituted cycloalkylalkoxy, substituted or unsubstituted heterocyclic group, substituted or unsubstituted hetero Cycloyloxy, substituted or unsubstituted aryl and substituted or unsubstituted aryloxy. Preferably, the term "substituted aryl" refers to an aryl group in which at least one hydrogen atom of the aryl group is replaced by a substituent selected from halogen and haloalkyl. Most preferably, "substituted aryl" refers to an aryl group in which 1 to 3 hydrogen atoms of the aryl group are replaced with a substituent selected from halogen and haloalkyl. Specific but non-limiting examples of substituted aryl groups are 4-fluorophenyl, 4-chlorophenyl, 2-chloro-4-fluoro-phenyl, 4-(trifluoromethyl)phenyl and 3,4 -Difluorophenyl.

The term "heteroaryl" refers to a monovalent or polyvalent, monocyclic, bicyclic or tricyclic ring having a total of 5 to 14 ring members, preferably 5 to 12 ring members and more preferably 5 to 10 ring members 2. Preferably a bicyclic ring system, wherein at least one ring in the system is aromatic, and at least one ring in the system contains one or more heteroatoms. Preferably, "heteroaryl" refers to a 5- to 10-membered heteroaryl group containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. Most preferably, "heteroaryl" refers to a 5- to 10-membered heteroaryl group containing 1 to 2 heteroatoms independently selected from O and N. Some non-limiting examples of heteroaryl groups include spiro[cyclopropane-1,3'-indoline] (e.g. spiro[cyclopropane-1,3'-indoline]-1'-yl), 2-pyridine Group, 3-pyridyl, 4-pyridyl, indol-1-yl, 1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-4-yl, 1H-indol -5-yl, 1H-indol-6-yl, 1H-indol-7-yl, 1,2-benzoxazol-3-yl, 1,2-benzoxazol-4-yl, 1 ,2-Benzoxazol-5-yl, 1,2-Benzoxazol-6-yl, 1,2-Benzoxazol-7-yl, 1H-indazol-3-yl, 1H-ind Azole-4-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-indazol-7-yl, pyrazol-1-yl, 1H-pyrazol-3-yl, 1H -Pyrazol-4-yl, 1H-pyrazol-5-yl, imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, oxazole- 2-yl, oxazol-4-yl and oxazol-5-yl. A particularly preferred but non-limiting example of a heteroaryl group is indolyl, specifically 1H-indol-3-yl. Heteroaryl groups can be substituted. Therefore, the term "substituted heteroaryl" refers to a heteroaryl in which at least one hydrogen atom of the heteroaryl is replaced by a substituent as described herein, preferably by a substituent selected from the group consisting of: halogen, Substituted or unsubstituted alkyl groups, cycloalkyl groups, heterocyclic groups and heterocyclic groups substituted with alkoxycarbonyl groups, wherein the substituted alkyl groups are substituted with 1 to 3 substituents selected from the group consisting of: halogen, hydroxyl , Heterocyclyl, trialkylsilyloxy, cycloalkyl, and heterocyclyl substituted with alkoxycarbonyl. Most preferably, "substituted heteroaryl" refers to a heteroaryl in which 1 to 2 hydrogen atoms of the heteroaryl are replaced by a substituent selected from the group consisting of halogen, substituted or unsubstituted alkyl, Cycloalkyl, heterocyclyl, and heterocyclyl substituted with alkoxycarbonyl, wherein the substituted alkyl is substituted with 1 to 3 substituents selected from halogen, hydroxy, heterocyclyl, trialkylsilicon Radicals, cycloalkyls, and heterocyclic groups substituted with alkoxycarbonyl. Specific but non-limiting examples of substituted heteroaryl groups are 5-methyl-1,2,4-oxadiazol-3-yl, 5-fluoro-1-methyl-indol-3-yl, 5 -Chloro-1-methyl-indol-3-yl, 5-chloro-1-cyclopropyl-indol-3-yl, 5-chloro-1-oxetanyl-indol-3-yl , 5-chloro-1-(oxetan-3-ylmethyl) indol-3-yl, 5-chloro-1-(2-hydroxyethyl) indol-3-yl, 1-(1 -Third-butoxycarbonylazetidin-3-yl)-5-chloro-indol-3-yl, 1-[(1-third-butoxycarbonylazetidin-3-yl)methyl Yl]-5-chloro-indol-3-yl, 5-(trifluoromethyl)-2-pyridyl, 5-(trifluoromethyl)-3-pyridyl, 4-(trifluoromethyl) Imidazol-1-yl, 4-(trifluoromethyl)pyrazol-1-yl, 4-tert-butylpyrazol-1-yl, 4-tert-butyloxazol-2-yl, 5-chloro -1-(cyclopropylmethyl) indol-3-yl, 6-fluoro-1H-indol-3-yl, 5-fluoro-1,2-benzoxazol-3-yl, 5-chloro -1H-indol-3-yl, 1-methylindazol-5-yl, 5-chloro-1-[1-(chloromethyl)-2-hydroxy-ethyl]indol-3-yl and 1-[2-[Third-butyl(dimethyl)silyl]oxyethyl]-5-chloro-indol-3-yl.

The term "hydroxyl" refers to the -OH group.

The term "cyano" refers to a -CN (nitrile) group.

The term "cycloalkylalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is replaced by a cycloalkyl group. Preferably, "cycloalkylalkyl" refers to an alkyl group in which one, two or three hydrogen atoms of the alkyl group, most preferably one hydrogen atom is replaced by a cycloalkyl group. A particularly preferred but non-limiting example of cycloalkylalkyl is cyclopropylmethyl.

The term "haloalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is replaced by a halogen atom, preferably fluorine. Preferably, "haloalkyl" refers to an alkyl group in which 1, 2, or 3 hydrogen atoms of the alkyl group are replaced by halogen atoms, preferably fluorine. Particularly preferred but non-limiting examples of haloalkyl are trifluoromethyl and trifluoroethyl.

The term "haloalkoxy" refers to an alkoxy group in which at least one hydrogen atom of the alkoxy group is replaced by a halogen atom, preferably fluorine. Preferably, "haloalkoxy" refers to an alkoxy group in which 1, 2, or 3 hydrogen atoms of the alkoxy group are replaced by halogen atoms, preferably fluorine. A particularly preferred but non-limiting example of haloalkoxy is trifluoromethoxy (-OCF ₃ ).

The term "cycloalkylalkoxy" refers to an alkoxy group in which at least one hydrogen atom of the alkoxy group is replaced by a cycloalkyl group. Preferably, "cycloalkylalkoxy" refers to an alkoxy group in which one, two or three hydrogen atoms of the alkoxy group, most preferably one hydrogen atom is replaced by a cycloalkyl group. A particularly preferred but non-limiting example of cycloalkylalkoxy is cyclopropylmethoxy.

The term "cycloalkyloxyalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is replaced by a cycloalkyloxy group as defined herein. Preferably, "cycloalkyloxyalkyl" refers to an alkyl group in which one, two or three hydrogen atoms of the alkyl group, most preferably one hydrogen atom is replaced by a cycloalkyloxy group. A particularly preferred but non-limiting example of cycloalkyloxyalkyl is cyclopropoxymethyl.

The term "hydroxyalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is replaced by a hydroxyl group. Preferably, "hydroxyalkyl" refers to an alkyl group in which one, two, or three hydrogen atoms, and most preferably one hydrogen atom of the alkyl group is replaced by a hydroxyl group. Preferred but non-limiting examples of hydroxyalkyl are hydroxymethyl and hydroxyethyl (eg 2-hydroxyethyl). A particularly preferred but non-limiting example of hydroxyalkyl is hydroxymethyl.

The term "arylalkoxy" refers to an alkoxy group in which at least one hydrogen atom of the alkoxy group is replaced by an aryl group. Preferably, "arylalkoxy" refers to an alkoxy group in which one, two, or three hydrogen atoms of the alkoxy group, and most preferably one hydrogen atom is replaced by an aryl group. A particularly preferred but non-limiting example of arylalkoxy is benzyloxy.

The term "arylalkoxyalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is replaced by an arylalkoxy group as defined herein. Preferably, "arylalkoxyalkyl" refers to an alkyl group in which one, two or three hydrogen atoms of the alkyl group, most preferably one hydrogen atom is replaced by an arylalkoxy group. A particularly preferred but non-limiting example of arylalkoxyalkyl is benzyloxymethyl.

The term "alkoxyalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is replaced by an alkoxy group. Preferably, "alkoxyalkyl" refers to an alkyl group in which 1, 2, or 3 hydrogen atoms of the alkyl group, most preferably 1 hydrogen atom, are replaced by alkoxy groups. A particularly preferred but non-limiting example of alkoxyalkyl is 2-methoxyethyl.

The term "alkoxycarbonyl" refers to the group alkyl-O-C(O)- (ie alkyl ester).

The term "trialkylsilyloxy" refers to the group (alkyl) ₃ Si-O-. A particularly preferred but non-limiting example of trialkylsilyloxy is [third butyl (dimethyl)silyl]oxy.

The term "haloaryl" refers to an aryl group in which at least one hydrogen atom of the aryl group is replaced by a halogen atom. Preferably, "haloaryl" refers to an aryl in which one, two, or three hydrogen atoms, more preferably one or two hydrogen atoms, and most preferably one hydrogen atom is replaced by a halogen atom base. A particularly preferred but non-limiting example of a halogenated aryl group is fluorophenyl, specifically 4-fluorophenyl.

The term "pharmaceutically acceptable salts" refers to those salts that retain the biological effectiveness and properties of free bases or free acids, which are not biologically or otherwise undesirable. Salts are composed of inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, especially hydrochloric acid) and organic acids (such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, Succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetyl cysteine and the like) . In addition, these salts can be prepared by adding an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, and the like. Salts derived from organic bases include (but are not limited to) the following salts: primary amines, secondary amines and tertiary amines, substituted amines including natural substituted amines, cyclic amines, and alkali ion exchange resins (eg Isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylhexahydropyridine, hexahydropyridine, polyimide resin and the like). The specific pharmaceutically acceptable salt of the compound of formula (I) is the hydrochloride salt.

The term "pharmaceutically acceptable ester" refers to an ester hydrolyzed in vivo and includes those that are easily decomposed in the human body to leave the parent compound or its salt. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids (specifically alkanoic acid, alkenoic acid, naphthenic acid and alkanedioic acid), where each alkyl or alkene The base portion advantageously has no more than 6 carbon atoms. Representative examples of specific esters include, but are not limited to, formate, acetate, propionate, butyrate, acrylate, and ethylsuccinate. Examples of pharmaceutically acceptable prodrug types are described in Higuchi and Stella, Pro-drugs as Novel Delivery Systems, A.C.S. Symposium Series No. 14 and Roche editors, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987.

The term "protecting group" (PG) means that it has the meaning commonly used in synthetic chemistry and selectively blocks the reactive site in the polyfunctional compound so that the chemical reaction can be at another unprotected reactive site Groups implemented selectively. The protecting group can be removed at an appropriate time. Exemplary protecting groups are amine protecting groups, carboxyl protecting groups or hydroxyl protecting groups. Specific protecting groups are the third butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), oxymethylmethoxycarbonyl (Fmoc) and benzyl (Bn). Other specific protecting groups are the third butoxycarbonyl (Boc) and oxymethylmethoxycarbonyl (Fmoc). A more specific protecting group is the third butoxycarbonyl (Boc). Exemplary protecting groups and their applications in organic synthesis are described in, for example, T. W. Greene and P. G. M. Wutts, "Protective Groups in Organic Chemistry", 5th Edition, 2014, John Wiley & Sons, N.Y.

The term "urea-forming reagent" refers to a compound that enables the first amine to react with the second amine, thereby forming a urea derivative. Non-limiting examples of urea-forming reagents include bis(trichloromethyl) carbonate, phosgene, trichloromethyl chloroformate, (4-nitrophenyl) carbonate, and 1,1′-carbonyldiimidazole. The urea-forming reagents described in G. Sartori et al., Green Chemistry 2000 , 2 , 140 are incorporated herein by reference.

Compounds of formula (I) may contain several asymmetric centers and may be optically pure mirror isomers, mixtures of mirror isomers (e.g. racemates), optically pure mirror isomers, mixtures of mirror isomers, mirrorless Heterogeneous racemates or mixtures of non-mirromeric isomers exist.

According to the Cahn-Ingold-Prelog convention, asymmetric carbon atoms can have an "R" or "S" configuration.

The abbreviation "MAGL" refers to the enzyme monoacylglycerol lipase. The terms "MAGL" and "monoacylglycerol lipase" are used interchangeably herein.

The term "treatment" as used herein includes: (1) an inhibitory state, disorder or condition (eg, in the case of maintenance therapy, preventing, reducing or delaying the development of the disease or its recurrence or at least one clinical or subclinical symptom thereof ); and/or (2) Alleviate the condition (ie, resolve at least one of the state, disorder or condition, or its clinical or subclinical symptoms).

The benefit to the patient to be treated is statistically significant or at least noticeable to the patient or physician. However, it should be understood that when a drug is administered to a patient to treat a disease, the result may not always be an effective treatment.

The term "prevention" as used herein includes: preventing or delaying the occurrence of clinical symptoms of a state, disorder, or condition occurring in mammals and especially humans, who may or may be susceptible to the state, disorder, or Symptoms but have not experienced or exhibited clinical or subclinical symptoms of the state, disorder or condition.

The term "neurological inflammation" as used herein refers to acute and chronic inflammation of nervous tissue, which is the main tissue component of two parts of the nervous system; the brain and spinal cord of the central nervous system (CNS) and the peripheral nervous system (PNS) branch of the peripheral nerve. Chronic neuroinflammation is associated with neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Acute neuroinflammation usually occurs immediately after the central nervous system is damaged (for example due to traumatic brain injury (TBI)).

The term "traumatic brain injury" ("TBI", also known as "intracranial injury") refers to damage to the brain caused by external mechanical forces, such as rapid acceleration or deceleration, shock, explosion waves or Projectile penetration.

The term "neurodegenerative diseases" refers to diseases related to the progressive loss of the structure or function of neurons (including the death of neurons). Examples of neurodegenerative diseases include, but are not limited to, multiple sclerosis, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.

The term "mental disorder" (also known as mental illness or mental disorder) refers to behaviors or mental patterns that can cause pain or poor ability to live. These characteristics can be persistent, relapse and remission, or occur as a single episode. Examples of mental disorders include (but are not limited to) anxiety and depression.

The term "pain" refers to unpleasant feelings and emotional experiences associated with actual or potential tissue damage. Examples of pain include, but are not limited to, nociceptive pain, chronic pain (including idiopathic pain), neuropathic pain (including chemotherapy-induced neuropathy), hallucinatory pain, and psychogenic pain. A specific example of pain is neuropathic pain, which is caused by damage or disease that affects any part of the nervous system (i.e., the somatosensory system) that involves body sensation. In one embodiment, "pain" is neuropathic pain resulting from amputation or thoracotomy. In one embodiment, "pain" is a neuropathy induced by chemotherapy.

The term "neurotoxicity" refers to toxicity in the nervous system. This happens when exposure to natural or artificial toxic substances (neurotoxins) alters the normal activity of the nervous system in a way that causes damage to nerve tissue. Examples of neurotoxicity include, but are not limited to, substances used in exposure to chemotherapy, radiation therapy, drug therapy, drug abuse, and organ transplantation, as well as exposure to heavy metals, certain foods and food additives, insecticides, industrial and /Or neurotoxicity caused by cleaning solvents, cosmetics and some natural substances.

The term "cancer" refers to a disease characterized by the presence of neoplasms or tumors caused by abnormal and uncontrolled growth of cells (these cells are "cancer cells"). As used herein, the term cancer specifically includes, but is not limited to, hepatocellular carcinoma, colon cancer occurrence, and ovarian cancer.

The term "mammal" as used herein includes both humans and non-humans, and includes (but is not limited to) humans, non-human primates, dogs, cats, rodents, cattle, horses, and pigs. In a particularly preferred embodiment, the term "mammal" refers to humans.

其中： L係選自-CR¹ R² -(CH₂ )_p -、-(CH₂ )_p -CR¹ R² -、-OCR³ R⁴ -、-CR³ R⁴ O-及共價鍵； m係1，n係1或2且X係CH；或 m係2，n係2或3且X係CH或N； p係0、1或2； A係選自經取代或未經取代之芳基、經取代或未經取代之雜芳基、經取代或未經取代之環烷基及經取代或未經取代之雜環基； R¹ 係選自烷氧基、經取代或未經取代之烷基、氰基、鹵素、經取代或未經取代之環烷基、(經取代或未經取代之環烷基)烷氧基、經取代或未經取代之芳基及經取代或未經取代之雜芳基； R² 係氫或鹵素； 或R¹ 及R² 與其所連接之碳原子一起形成經取代或未經取代之環烷基或經取代或未經取代之雜環基； R³ 係選自經取代或未經取代之烷基、經取代或未經取代之環烷基及經取代或未經取代之芳基； R⁴ 係氫； 或R³ 及R⁴ 與其所連接之碳原子一起形成經取代或未經取代之環烷基或經取代或未經取代之雜環基； 其中： 每一經取代之烷基獨立地經一或多個獨立地選自以下之取代基取代：鹵素、羥基、烷氧基、芳基烷氧基、三烷基矽基氧基、經取代或未經取代之環烷基、經取代或未經取代之環烷基氧基及經取代或未經取代之雜環基； 每一經取代之芳基、經取代之雜芳基、經取代之環烷基、經取代之環烷基氧基及經取代之雜環基獨立地經一或多個獨立地選自以下之取代基取代：鹵素、氰基、烷氧基、鹵代烷氧基、經取代或未經取代之烷基、經R⁵ 、R⁶ 及R⁷ 取代之環烷基、經R^5a 、R^6a 及R^7a 取代之環烷基氧基、經R^5b 、R^6b 及R^7b 取代之環烷基烷氧基、經R⁸ 、R⁹ 及R¹⁰ 取代之雜環基、經R^8a 、R^9a 及R^10a 取代之雜環基氧基及經R¹¹ 、R¹² 及R¹³ 取代之芳基；且 R⁵ 、R⁶ 、R⁷ 、R^5a 、R^6a 、R^7a 、R^5b 、R^6b 、R^7b 、R⁸ 、R⁹ 、R¹⁰ 、R^8a 、R^9a 、R^10a 、R¹¹ 、R¹² 及R¹³ 中之每一者獨立地選自氫、鹵素、烷氧基、鹵代烷氧基、烷氧基羰基及經取代或未經取代之烷基； 或其醫藥上可接受之鹽或酯。 Compounds of the invention In the first aspect, the invention provides compounds of formula (I)

Among them: L series is selected from -CR ¹ R ² -(CH ₂ ) _p -, -(CH ₂ ) _p -CR ¹ R ² -, -OCR ³ R ⁴ -, -CR ³ R ⁴ O- and covalent bond ; M is 1, n is 1 or 2 and X is CH; or m is 2, n is 2 or 3 and X is CH or N; p is 0, 1 or 2; A is selected from substituted or unsubstituted Aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl; R ¹ is selected from alkoxy, substituted or unsubstituted Substituted alkyl, cyano, halogen, substituted or unsubstituted cycloalkyl, (substituted or unsubstituted cycloalkyl) alkoxy, substituted or unsubstituted aryl and substituted Or unsubstituted heteroaryl; R ² is hydrogen or halogen; or R ¹ and R ² together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycle R ³ is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted aryl; R ⁴ is hydrogen; or R ³ and R ⁴ are The connected carbon atoms together form a substituted or unsubstituted cycloalkyl group or a substituted or unsubstituted heterocyclic group; wherein: each substituted alkyl group is independently selected by one or more of the following Substituent substitution: halogen, hydroxy, alkoxy, arylalkoxy, trialkylsilyloxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyloxy and Substituted or unsubstituted heterocyclyl; each substituted aryl, substituted heteroaryl, substituted cycloalkyl, substituted cycloalkyloxy, and substituted heterocyclyl independently One or more substituents independently selected from the group consisting of halogen, cyano, alkoxy, haloalkoxy, substituted or unsubstituted alkyl, cycloalkane substituted with R ⁵ , R ⁶ and R ^{7 Group} , cycloalkyloxy substituted with R ^5a , R ^6a and R ^7a , cycloalkylalkoxy substituted with R ^5b , R ^6b and R ^7b , heterocyclic ring substituted with R ⁸ , R ⁹ and R ^{10 Radicals} , heterocyclyloxy substituted by R ^8a , R ^9a and R ^10a and aryl substituted by R ¹¹ , R ¹² and R ¹³ ; and R ⁵ , R ⁶ , R ⁷ , R ^5a , R ^6a , R ^{Each of 7a} , R ^5b , R ^6b , R ^7b , R ⁸ , R ⁹ , R ¹⁰ , R ^8a , R ^9a , R ^10a , R ¹¹ , R ¹² and R ¹³ is independently selected from hydrogen, halogen, Alkoxy, haloalkoxy, alkoxycarbonyl and substituted or unsubstituted alkyl; or a pharmaceutically acceptable salt or ester thereof.

其中A、L、X、m及n係如本文所闡述。In one embodiment, there is provided a compound of formula (I) as set forth herein, wherein the compound of formula (I) is a compound of formula (Ia):

Among them, A, L, X, m and n are as described in this article.

其中A、L、X、m及n係如本文所闡述。In one embodiment, there is provided a compound of formula (I) as set forth herein, wherein the compound of formula (I) is a compound of formula (Ib):

Among them, A, L, X, m and n are as described in this article.

In one embodiment, there is provided a compound of formula (I) as described herein, wherein: L is selected from -CR ¹ R ² -(CH ₂ ) _p -, -(CH ₂ ) _p -CR ¹ R ² -, ^{-OCR 3 R 4 -, - CR} 3 R 4 O- , and a covalent bond; m lines 1, n 1 or 2 and X-based system CH; m based or 2, n 2, or 3 and X based system CH or N; p is 0, 1 or 2; A is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted Heterocyclic group; wherein: the substituted aryl group is substituted with one or more, preferably 1 to 3, more preferably 1 to 2 substituents, specifically 1 substituent, the (etc.) substitution The radical is selected from halogen (specifically fluorine) and haloalkyl (specifically trifluoromethyl); the substituted heteroaryl group is one or more, preferably 1 to 3, more preferably 1 to 2 Substituents, specifically 2 substituents, the substituent(s) are selected from halogen, substituted or unsubstituted alkyl, cycloalkyl, heterocyclic, and alkoxycarbonyl substituted hetero Cyclic; wherein: substituted alkyl is substituted with one or more substituents selected from the group consisting of hydroxy, cycloalkyl, heterocyclyl, trialkylsilyloxy, halogen and alkoxycarbonyl substituted Heterocyclic group; substituted cycloalkyl is substituted with one or more, preferably 1 to 3, more preferably 1 to 2 substituents, specifically 1 substituent, the (etc.) substituent is Selected from haloaryl and haloalkylaryl; and the substituted heterocyclic group is substituted with one or more, preferably 1 to 3, more preferably 1 to 2 substituents selected from: substituted Or unsubstituted alkyl, halogen and alkoxy; wherein: substituted alkyl is substituted with one or more, preferably 1 to 3 substituents selected from the group consisting of hydroxy, halogen, alkoxy, Arylalkoxy and cycloalkyl; R ¹ is selected from alkoxy, alkoxyalkyl, hydroxyalkyl, alkyl, cyano, halogen, cycloalkyl, cycloalkylalkoxy, hydroxyalkyl Group, halogenated alkyl group, substituted or unsubstituted aryl group and substituted or unsubstituted heteroaryl group; wherein: the substituted aryl group is one or more, preferably 1 to 3, more preferably 1 to 2 substituents, specifically 1 substituent, the substituent(s) are selected from halogen; and the substituted heteroaryl is substituted by one or more, preferably 1 to 3, More preferably, 1 to 2 substituents, specifically 1 substituent, the substituent(s) are selected from alkyl; R ² is hydrogen or halogen; or R ¹ and R ² and the carbon atom to which they are attached Together form cycloalkyl or heterocyclyl; R ³ is selected from alkyl, cycloalkyl and aryl; and R ⁴ is hydrogen; or R ³ and R ⁴ together with the carbon atom to which they are attached form cycloalkyl or hetero Ring base. In one embodiment, the present invention provides compounds of formula (I) as described herein, wherein: L is selected from -CR ¹ R ² -(CH ₂ ) _p -, -(CH ₂ ) _p -CR ¹ R ² -, -OCR ³ R ⁴ -, -CR ³ R ⁴ O- and covalent bonds; m series 1, n series 1 or 2 and X series CH; or m series 2, n series 2 or 3 and X series CH or N; p is 0, 1 or 2; A is selected from substituted or unsubstituted C _6-10 -aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C _{3- 8} -cycloalkyl and substituted or unsubstituted heterocyclic group; R ¹ is selected from C _1-6 -alkoxy, substituted or unsubstituted C _1-6 -alkyl, cyano, halogen , Substituted or unsubstituted C _3-8 -cycloalkyl, (substituted or unsubstituted C _3-8 -cycloalkyl) C _1-6 -alkoxy, substituted or unsubstituted C _6-10 -aryl and substituted or unsubstituted heteroaryl; R ² is hydrogen or halogen; or R ¹ and R ² together with the carbon atom to which they are attached form a substituted or unsubstituted C _{3- 8} -cycloalkyl or substituted or unsubstituted heterocyclic group; R ³ is selected from substituted or unsubstituted C _1-6 -alkyl, substituted or unsubstituted C _{3-8 -ring} Alkyl and substituted or unsubstituted C _6-10 -aryl; and R ⁴ is hydrogen; or R ³ and R ⁴ together with the carbon atom to which they are attached form a substituted or unsubstituted C _3-8- Cycloalkyl or substituted or unsubstituted heterocyclyl; wherein: each substituted C _1-6 -alkyl is independently substituted with one or more substituents independently selected from halogen, hydroxy, C _1-6 -alkoxy, C _6-10 -aryl-C _1-6 -alkoxy, tri(C _1-6 -alkyl)silyloxy, substituted or unsubstituted C _{3- 8} -cycloalkyl and substituted or unsubstituted heterocyclic groups; and each substituted C _6-10 -aryl, substituted heteroaryl, substituted C _3-8 -cycloalkyl and The substituted heterocyclic group is independently substituted with one or more substituents independently selected from the group consisting of halogen, C _1-6 -alkoxy, substituted or unsubstituted C _1-6 -alkyl, and R ⁵ , C _3-8 -cycloalkyl substituted with R ⁶ and R ⁷ , cycloalkyloxy substituted with R ^5a , R ^6a and R ^7a , cycloalkyl alkyl substituted with R ^5b , R ^6b and R ^7b Oxy, heterocyclyl substituted with R ⁸ , R ⁹ and R ¹⁰ , heterocyclic oxy substituted with R ^8a , R ^9a and R ^10a and aryl substituted with R ¹¹ , R ¹² and R ¹³ ; and R ⁵ , R ⁶ , R ⁷ , R ^5a , R ^6a , R ^7a , R ^5b , R ^6b , R ^7b , R ⁸ , R ⁹ , R ¹⁰ , R ^8a , R ^9a , R ^10a , R ¹¹ , R ¹² and R ¹³ are each independently selected from hydrogen, halogen, C _1-6 -alkoxy, C _1-6 -haloalkoxy, C _1-6 -Alkoxycarbonyl and substituted or unsubstituted C _1-6 -alkyl; each "heteroaryl" represents a monocyclic or bicyclic ring system with a total of 5 to 10 ring members, at least at least One ring is aromatic, and at least one ring in the system contains 1 to 2 heteroatoms independently selected from O and N; and each "heterocyclyl" represents a saturation or part with 3 to 8 ring atoms Unsaturated monocyclic or bicyclic ring systems, one to two of these ring atoms are heteroatoms selected from O and N, and the remaining ring atoms are carbon; or a pharmaceutically acceptable salt or ester thereof.

In one embodiment, there is provided a compound of formula (I) as set forth herein, wherein: L is a covalent bond; and A is selected from aryl, substituted heteroaryl, substituted or unsubstituted heterocyclyl and substituted cycloalkyl; wherein The substituted heteroaryl group is substituted with 1 to 2 substituents independently selected from the group consisting of substituted or unsubstituted alkyl, halogen, and cycloalkyl, wherein the substituted heterocyclic group is Substituted substituents of substituted alkyl groups; and wherein each substituted alkyl group is independently substituted with 1 to 3 substituents independently selected from the group consisting of cycloalkyl, heterocyclyl, hydroxyl, and trialkylsilyloxy base. In one embodiment, there is provided a compound of formula (I) as set forth herein, wherein: L is a covalent bond; and A is selected from aryl and substituted heteroaryl; wherein The substituted heteroaryl group is substituted with 1 to 2 substituents independently selected from the group consisting of substituted or unsubstituted alkyl, alkoxy, haloalkoxy, halogen, and cycloalkyl; and The substituted alkyl is independently substituted with 1 to 3 substituents independently selected from the group consisting of cycloalkyl, heterocyclic, hydroxy, halogen, and trialkylsilyloxy.

In a preferred embodiment, a compound of formula (I) as described herein is provided, wherein: L is a covalent bond; and A is a heteroaryl group substituted with two substituents independently selected from the group consisting of halogen, alkyl, cycloalkyl, cycloalkylalkyl, and heterocyclic group.

In another preferred embodiment, a compound of formula (I) as described herein is provided, wherein: L is a covalent bond; and A is a heteroaryl group, which is substituted with two substituents independently selected from the group consisting of chlorine, methyl, cyclopropyl, cyclopropylmethyl, and oxetanyl.

In another preferred embodiment, a compound of formula (I) as described herein is provided, wherein: L is a covalent bond; and A is indolyl, which is substituted with two substituents independently selected from the group consisting of chlorine, methyl, cyclopropyl, cyclopropylmethyl and oxetanyl.

In particularly preferred embodiments, compounds of formula (I) as provided herein are provided, wherein: L is a covalent bond; and A is selected from 5-chloro-1-(cyclopropylmethyl) indol-3-yl, 5-chloro-1-methyl-indol-3-yl, 5-chloro-1-cyclopropyl- Indol-3-yl and 5-chloro-1-(oxetan-3-yl) indol-3-yl.

In one embodiment, a compound of formula (I) as described herein is provided, wherein: L is -CHR ¹ -; R ¹ is as defined herein; and A is selected from substituted or unsubstituted aryl , Heteroaryl, heterocyclic and cycloalkyl substituted with one haloalkyl, wherein the substituted aryl is substituted with 1 to 2 substituents selected from halogen and haloalkyl.

In a preferred embodiment, a compound of formula (I) as described herein is provided, wherein: L is -CHR ¹ -; R ¹ is as defined herein; and A is selected from aryl and 1 to 2 Aryl substituted by a substituent selected from halogen and haloalkyl.

In another preferred embodiment, a compound of formula (I) as described herein is provided, wherein: L is -CHR ¹ -; R ¹ is as defined herein; and A is selected from aryl and Two aryl groups substituted with substituents selected from fluorine, chlorine and trifluoromethyl (CF ₃ ).

In another preferred embodiment, there is provided a compound of formula (I) as described herein, wherein: L is -CHR ¹ -; R ¹ is as defined herein; and A is selected from phenyl and 1 to Two phenyl groups substituted with substituents selected from fluorine, chlorine and trifluoromethyl (CF ₃ ).

In a particularly preferred embodiment, a compound of formula (I) as described herein is provided, wherein: L is -CHR ¹ -; R ¹ is as defined herein; and A is selected from phenyl, 4-fluorophenyl , 4-chlorophenyl, 2-chloro-4-fluoro-phenyl and 4-(trifluoromethyl)phenyl.

In one embodiment, a compound of formula (I) as described herein is provided, wherein: L is -CR ¹ R ² -(CH ₂ ) _p -, -OCHR ³ -or a covalent bond; p is 0 or 1; R ¹ is selected from alkoxy, alkoxyalkyl, hydroxyalkyl, alkyl, cyano, halogen, aryl and haloaryl; R ² is selected from hydrogen and halogen; and R ³ is alkyl .

In a preferred embodiment, a compound of formula (I) as described herein is provided, wherein: L is -CR ¹ R ² -, -OCHR ³ -or a covalent bond; R ¹ is selected from alkoxyalkyl, Hydroxyalkyl, aryl, halogenated aryl and halogen; R ² is selected from hydrogen and halogen; and R ³ is alkyl.

In a particularly preferred embodiment, a compound of formula (I) as described herein is provided, wherein: L is -CR ¹ R ² -, -OCHR ³ -or a covalent bond; R ¹ is selected from methoxyethyl, Hydroxyethyl, phenyl, fluorophenyl and fluorine; R ² is selected from hydrogen and fluorine; and R ³ is methyl.

In another particularly preferred embodiment, a compound of formula (I) as described herein is provided, wherein: L is -CR ¹ R ² -, -OCHR ³ -or a covalent bond; R ¹ is selected from 2-methoxy Ethyl, 2-hydroxyethyl, phenyl, 4-fluorophenyl and fluorine; R ² is selected from hydrogen and fluorine; and R ³ is methyl.

In another particularly preferred embodiment, L is -CF ₂ -. In one embodiment, L is -CHR ¹ -or a covalent bond, wherein R ¹ is as defined herein.

In one embodiment, R ¹ is selected from aryl, halogen, alkoxyalkyl, alkoxy, haloaryl, alkyl, and hydroxyalkyl.

In one embodiment, R ¹ is selected from phenyl, fluorine, 2-methoxyethyl, methoxy, methyl, 4-fluorophenyl, and 2-hydroxyethyl.

In one embodiment, R ² is hydrogen or halogen.

In one embodiment, R ² is hydrogen or fluorine.

In one embodiment, R ³ is alkyl.

In one embodiment, R ³ is methyl.

In one embodiment, R ⁴ is hydrogen.

In one embodiment, p is 0 or 1.

In one embodiment, p is 0.

In one embodiment, there is provided a compound of formula (I) as set forth herein, wherein: A is selected from substituted or unsubstituted aryl and substituted heteroaryl; wherein the substituted aryl is substituted with one or more substituents selected from halogen and haloalkyl; and wherein the substituted The heteroaryl group is substituted with one or more substituents selected from the group consisting of halogen, substituted or unsubstituted alkyl, alkoxy, haloalkoxy, cycloalkyl, and heterocyclyl; and wherein the substituted The alkyl group is substituted with one or more substituents selected from the group consisting of hydroxy, cycloalkyl, heterocyclyl, trialkylsilyloxy and halogen.

In a preferred embodiment, a compound of formula (I) as described herein is provided, wherein: A is selected from substituted aryl and substituted heteroaryl; wherein the substituted heteroaryl is substituted by one or more substituents, preferably 2 substituents, the (etc.) substituent is selected From halogen, alkyl, cycloalkyl, cycloalkylalkyl, and heterocyclic groups; and wherein the substituted aryl group is substituted with one or more substituents, preferably 1 to 2 substituents, the (etc. ) The substituent is selected from halogen and haloalkyl.

In a particularly preferred embodiment, a compound of formula (I) as described herein is provided, wherein: A is selected from substituted aryl and substituted indolyl; wherein the substituted indolyl is substituted by one or more Substituents, preferably 2 substituents, the substituent(s) are selected from cyclopropyl, chloro, methyl, cyclopropylmethyl and oxetanyl; and wherein the substituted benzene The group is substituted with one or more substituents, preferably 1 to 2 substituents, and the substituent(s) is selected from chlorine, fluorine, and trifluoromethyl (CF ₃ ).

In another particularly preferred embodiment, compounds of formula (I) as described herein are provided, wherein: A is selected from 5-chloro-1-(cyclopropylmethyl) indol-3-yl, 5-chloro-1-methyl-indol-3-yl, 5-chloro-1-cyclopropyl- Indol-3-yl, 5-chloro-1-(oxetan-3-yl) indol-3-yl, 4-fluorophenyl, 2-chloro-4-fluoro-phenyl, 4-( Trifluoromethyl)phenyl and 4-chlorophenyl.

In another particularly preferred embodiment, compounds of formula (I) as described herein are provided, wherein: A is selected from 5-chloro-1-(cyclopropylmethyl) indol-3-yl; 5-chloro-1-methyl-indol-3-yl; 9H-fu-9-9-yl; 6- Fluoro-1H-indol-3-yl; 5-fluoro-1,2-benzoxazol-3-yl; 5-chloro-1H-indol-3-yl; 1-methylindazol-5- Group; 5-chloro-1-cyclopropyl-indol-3-yl; 5-chloro-1-[1-(chloromethyl)-2-hydroxy-ethyl] indol-3-yl; 5- Chloro-1-(oxetan-3-yl) indol-3-yl; 5-chloro-1-(oxetan-3-ylmethyl) indol-3-yl; 1-[2 -[T-butyl(dimethyl)silyl]oxyethyl]-5-chloro-indol-3-yl; 5-chloro-1-(2-hydroxyethyl)indol-3-yl ; 5-(trifluoromethyl)-3-pyridyl; 5-methoxy-3-pyridyl; 5-(trifluoromethoxy)-2-pyridyl; 5-ethyl-3-pyridyl ; 5-(1,1-difluoroethyl)-2-pyridyl; 6-chloro-1-methyl-indazol-3-yl; phenyl; 4-fluorophenyl; 4-chlorophenyl; Cyano(phenyl)methyl; 4-(trifluoromethyl)phenyl; and 2-chloro-4-fluoro-phenyl.

In a preferred embodiment, a compound of formula (I) as described herein is provided, wherein: Both m and n are 2; and X is CH or N.

In one embodiment, there is provided a compound of formula (I) as described herein, wherein: L is -CR ¹ R ² -(CH ₂ ) _p -, -OCHR ³ -or a covalent bond; both m and n Is 2; p is 0 or 1; X is CH or N; A is selected from substituted or unsubstituted aryl and substituted heteroaryl; wherein the substituted aryl is substituted by one or more substituents , Preferably 1 to 2 substituents are substituted, and the substituent(s) are selected from halogen and haloalkyl; and wherein the substituted heteroaryl is substituted with one or more substituents, preferably 2 substituents Substitution, the substituent(s) is selected from halogen, substituted or unsubstituted alkyl, alkoxy, haloalkoxy, cycloalkyl and heterocyclic; wherein the substituted alkyl is substituted by one or more Substituents, preferably 1 to 3 substituents, the substituent(s) are selected from hydroxyl, cycloalkyl, heterocyclyl, trialkylsilyloxy and halogen; R ¹ is selected from alkyl Oxygen, alkoxyalkyl, hydroxyalkyl, alkyl, cyano, halogen, aryl and haloaryl; R ² is selected from hydrogen and halogen; and R ³ is alkyl.

In a preferred embodiment, a compound of formula (I) as described herein is provided, wherein: L is -CR ¹ R ² -, -OCHR ³ -or a covalent bond; both m and n are 2; X is CH or N; A is selected from substituted aryl and substituted heteroaryl; wherein the substituted heteroaryl is substituted by one or more substituents, preferably 2 substituents, the (etc.) The substituent is selected from halogen, alkyl, cycloalkyl, cycloalkylalkyl, and heterocyclic group, and wherein the substituted aryl group is substituted with one or more substituents, preferably 1 to 2 substituents , The substituent(s) is selected from halogen and haloalkyl; R ¹ is selected from alkoxyalkyl, hydroxyalkyl, aryl, haloaryl and halogen; R ² is selected from hydrogen and halogen; and R ³ is an alkyl group.

In a particularly preferred embodiment, a compound of formula (I) as described herein is provided, wherein: L is -CR ¹ R ² -, -OCHR ³ -or a covalent bond; both m and n are 2; X is CH or N; A is selected from substituted phenyl and substituted indolyl; wherein the substituted indolyl is substituted with one or more substituents, preferably 2 substituents, the (etc.) The substituent is selected from cyclopropyl, chloro, methyl, cyclopropylmethyl and oxetanyl; and wherein the substituted phenyl is substituted by one or more substituents, preferably 1 to 2 Group substitution, the substituent group is selected from fluorine, chlorine and trifluoromethyl (CF ₃ ); R ¹ is selected from methoxyethyl, hydroxyethyl, phenyl, fluorophenyl and fluorine; R ² is selected from hydrogen and fluorine; and R ³ is methyl.

In another particularly preferred embodiment, a compound of formula (I) as described herein is provided, wherein: L is -CR ¹ R ² -, -OCHR ³ -or a covalent bond; both m and n are 2; X is CH or N; A is selected from 5-chloro-1-(cyclopropylmethyl) indol-3-yl, 5-chloro-1-methyl-indol-3-yl, 4-fluorobenzene Group, 4-chlorophenyl, 4-(trifluoromethyl)phenyl, 2-chloro-4-fluoro-phenyl, 5-chloro-1-cyclopropyl-indol-3-yl, 5-chloro -1-oxetanyl-indol-3-yl; R ¹ is selected from 2-methoxyethyl, 2-hydroxyethyl, phenyl, 4-fluorophenyl and fluorine; R ² is selected From hydrogen and fluorine; and R ³ is methyl.

其中： L係選自-CR¹ R² -(CH₂ )_p -、-(CH₂ )_p -CR¹ R² -、-OCR³ R⁴ -、-CR³ R⁴ O-及共價鍵； m係1，n係1或2且X係CH；或 m係2，n係2或3且X係CH或N； p係0、1或2； A係選自經取代或未經取代之芳基、經取代或未經取代之雜芳基、經取代或未經取代之環烷基及經取代或未經取代之雜環基； R¹ 係選自烷氧基、經取代或未經取代之烷基、氰基、鹵素、經取代或未經取代之環烷基、(經取代或未經取代之環烷基)烷氧基、經取代或未經取代之芳基及經取代或未經取代之雜芳基； R² 係氫或鹵素； 或R¹ 及R² 與其所連接之碳原子一起形成經取代或未經取代之環烷基或經取代或未經取代之雜環基； R³ 係選自經取代或未經取代之烷基、經取代或未經取代之環烷基及經取代或未經取代之芳基；且 R⁴ 係氫； 或R³ 及R⁴ 與其所連接之碳原子一起形成經取代或未經取代之環烷基或經取代或未經取代之雜環基； 其中： 每一經取代之烷基獨立地經一或多個獨立地選自以下之取代基取代：鹵素、羥基、烷氧基、芳基烷氧基、三烷基矽基氧基、經取代或未經取代之環烷基、經取代或未經取代之環烷基氧基及經取代或未經取代之雜環基； 每一經取代之芳基、經取代之雜芳基、經取代之環烷基、經取代之環烷基氧基及經取代之雜環基獨立地經一或多個獨立地選自以下之取代基取代：鹵素、氰基、烷氧基、鹵代烷氧基、經取代或未經取代之烷基、經R⁵ 、R⁶ 及R⁷ 取代之環烷基、經R^5a 、R^6a 及R^7a 取代之環烷基氧基、經R^5b 、R^6b 及R^7b 取代之環烷基烷氧基、經R⁸ 、R⁹ 及R¹⁰ 取代之雜環基、經R^8a 、R^9a 及R^10a 取代之雜環基氧基及經R¹¹ 、R¹² 及R¹³ 取代之芳基；且 R⁵ 、R⁶ 、R⁷ 、R^5a 、R^6a 、R^7a 、R^5b 、R^6b 、R^7b 、R⁸ 、R⁹ 、R¹⁰ 、R^8a 、R^9a 、R^10a 、R¹¹ 、R¹² 及R¹³ 中之每一者獨立地選自氫、鹵素、烷氧基、鹵代烷氧基、烷氧基羰基及經取代或未經取代之烷基； 或其醫藥上可接受之鹽或酯。The present invention also provides the following listed examples (E): E1: a compound of formula (I),

Among them: L series is selected from -CR ¹ R ² -(CH ₂ ) _p -, -(CH ₂ ) _p -CR ¹ R ² -, -OCR ³ R ⁴ -, -CR ³ R ⁴ O- and covalent bond ; M is 1, n is 1 or 2 and X is CH; or m is 2, n is 2 or 3 and X is CH or N; p is 0, 1 or 2; A is selected from substituted or unsubstituted Aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl; R ¹ is selected from alkoxy, substituted or unsubstituted Substituted alkyl, cyano, halogen, substituted or unsubstituted cycloalkyl, (substituted or unsubstituted cycloalkyl) alkoxy, substituted or unsubstituted aryl and substituted Or unsubstituted heteroaryl; R ² is hydrogen or halogen; or R ¹ and R ² together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycle R ³ is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted aryl; and R ⁴ is hydrogen; or R ³ and R ⁴ Together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkyl group or a substituted or unsubstituted heterocyclic group; wherein: each substituted alkyl group is independently selected by one or more of the following Substituent substitution: halogen, hydroxy, alkoxy, arylalkoxy, trialkylsilyloxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyloxy And substituted or unsubstituted heterocyclic groups; each substituted aryl, substituted heteroaryl, substituted cycloalkyl, substituted cycloalkyloxy, and substituted heterocyclyl are independently Substitution with one or more substituents independently selected from the group consisting of halogen, cyano, alkoxy, haloalkoxy, substituted or unsubstituted alkyl, and rings substituted with R ⁵ , R ⁶ and R ⁷ Alkyl, cycloalkyloxy substituted with R ^5a , R ^6a and R ^7a , cycloalkylalkoxy substituted with R ^5b , R ^6b and R ^7b , hetero substituted with R ⁸ , R ⁹ and R ¹⁰ Ring group, heterocyclyloxy group substituted with R ^8a , R ^9a and R ^10a and aryl group substituted with R ¹¹ , R ¹² and R ¹³ ; and R ⁵ , R ⁶ , R ⁷ , R ^5a , R ^6a , Each of R ^7a , R ^5b , R ^6b , R ^7b , R ⁸ , R ⁹ , R ¹⁰ , R ^8a , R ^9a , R ^10a , R ¹¹ , R ¹² and R ¹³ is independently selected from hydrogen, halogen , Alkoxy, haloalkoxy, alkoxycarbonyl and substituted or unsubstituted alkyl; or a pharmaceutically acceptable salt or ester thereof.

其中A、L、X、m及n係如技術方案1中所定義。E2: A compound of formula (I) as E1, wherein the compound of formula (I) is a compound of formula (Ia):

Wherein A, L, X, m and n are as defined in technical solution 1.

其中A、L、X、m及n係如技術方案1中所定義。E3: The compound of formula (I) as E1, wherein the compound of formula (I) is a compound of formula (Ib):

Wherein A, L, X, m and n are as defined in technical solution 1.

E4: Compound of formula (I) as in any one of E1 to E3, wherein: L is -CR ¹ R ² -(CH ₂ ) _p -, -OCHR ³ -or covalent bond; p is 0 or 1; R ¹ is selected from alkoxy, alkyl, alkoxyalkyl, hydroxyalkyl, cyano, halogen, aryl and haloaryl; R ² is selected from hydrogen and halogen; and R ³ is alkyl.

E5: Compound of formula (I) as in any one of E1 to E3, wherein: L is -CR ¹ R ² -, -OCHR ³ -or covalent bond; R ¹ is selected from alkoxyalkyl, hydroxyalkane Group, aryl, halogenated aryl and halogen; R ² is selected from hydrogen and halogen; and R ³ is alkyl.

E6: Compound of formula (I) as in any one of E1 to E3, wherein: L is -CR ¹ R ² -, -OCHR ³ -or covalent bond; R ¹ is selected from methoxyethyl, hydroxyethyl Radical, phenyl, fluorophenyl and fluorine; R ² is selected from hydrogen and fluorine; and R ³ is methyl.

E7: Compound of formula (I) as in any one of E1 to E6, wherein: A is selected from substituted or unsubstituted aryl and substituted heteroaryl; wherein: The substituted aryl group is substituted with one or more substituents selected from halogen and haloalkyl; and The substituted heteroaryl group is substituted with one or more substituents selected from the group consisting of halogen, substituted or unsubstituted alkyl, alkoxy, haloalkoxy, cycloalkyl, and heterocyclyl; wherein: The substituted alkyl is substituted with one or more substituents selected from the group consisting of hydroxy, cycloalkyl, heterocyclyl, trialkylsilyloxy, and halogen.

E8: Compound of formula (I) as in any one of E1 to E6, wherein: A is selected from halogenated aryl and substituted heteroaryl; where: The substituted heteroaryl group is substituted with one or more substituents selected from the group consisting of halogen, alkyl, cycloalkyl, cycloalkylalkyl, and heterocyclic group.

E9: Compound of formula (I) as in any one of E1 to E6, wherein: A is selected from fluorophenyl, chlorophenyl and substituted indolyl, wherein: The substituted indolyl is substituted with one or more substituents selected from cyclopropyl, chloro, methyl, cyclopropylmethyl and oxetanyl.

E10: A compound of formula (I) as in any one of E1 to E9, wherein both m and n are 2 and X is CH or N.

E11: A compound of formula (I) as in any one of E1 to E3, wherein: L is -CR ¹ R ² -(CH ₂ ) _p -, -OCHR ³ -or a covalent bond; both m and n are 2; p is 0 or 1; X is CH or N; A is selected from substituted or unsubstituted aryl and substituted heteroaryl; wherein: the substituted aryl is selected from one or more Halogen and haloalkyl substituents are substituted; and the substituted heteroaryl is substituted with one or more substituents selected from halogen, substituted or unsubstituted alkyl, alkoxy, haloalkoxy, Cycloalkyl and heterocyclyl; wherein the substituted alkyl is substituted with one or more substituents selected from the group consisting of hydroxy, cycloalkyl, heterocyclyl, trialkylsilyloxy and halogen; R ¹ It is selected from alkoxy, alkoxyalkyl, alkyl, hydroxyalkyl, cyano, halogen, aryl and haloaryl; R ² is selected from hydrogen and halogen; and R ³ is alkyl.

E12: A compound of formula (I) as in any one of E1 to E3, wherein: L is -CR ¹ R ² -, -OCHR ³ -or a covalent bond; both m and n are 2; X is CH or N; A is selected from halogenated aryl and substituted heteroaryl; wherein: the substituted heteroaryl is substituted by one or more substituents selected from halogen, alkyl, cycloalkyl, cyclic Alkyl alkyl and heterocyclic groups; R ¹ is selected from alkoxyalkyl, hydroxyalkyl, aryl, halogen and halogenated aryl. R ² is selected from hydrogen and halogen; and R ³ is alkyl.

E13: A compound of formula (I) as in any one of E1 to E3, wherein: L is -CR ¹ R ² -, -OCHR ³ -or a covalent bond; both m and n are 2; X is CH or N; A is selected from fluorophenyl, chlorophenyl and substituted indolyl, wherein: the substituted indolyl is substituted with one or more substituents selected from the group consisting of cyclopropyl, chloro, methyl Group, cyclopropylmethyl and oxetanyl; and R ¹ is selected from methoxyethyl, hydroxyethyl, phenyl, fluorine and fluorophenyl. R ² is selected from hydrogen and fluorine; and R ³ is methyl.

或其醫藥上可接受之鹽，其中： L 係選自-CR¹ R² -(CH₂ )_p -、-(CH₂ )_p -CR¹ R² -、-OCR³ R⁴ -、-CR³ R⁴ O-及共價鍵； m係0，n係0或1且X係CR²⁴ ；或 m係1，n係1或2且X係CR²⁴ 或N； p 係0、1或2； R¹ 係選自鹵素、C_1-6 -烷氧基、C_1-6 -烷基、鹵基-C_1-6 -烷基、羥基-C_1-6 -烷基、C_1-6 -烷氧基-C_1-6 -烷基-、鹵基-C_1-6 -烷氧基、鹵基-C_1-6 -烷氧基-C_1-6 -烷基-、氰基及基團

；且R² 係選自氫、鹵素及羥基；或 R¹ 及R² 與其所連接之碳原子一起形成C_3-12 -環烷基或C_2-9 -雜環基； R³ 係選自C_1-6 -烷基、鹵基-C_1-6 -烷基、C_3-12 -環烷基及C_6-14 -芳基；且R⁴ 係氫；或 R³ 及R⁴ 與其所連接之碳原子一起形成C_3-12 -環烷基或C_2-9 -雜環基； R²⁰ 係氫或C_1-6 -烷基； R²¹ 、R²² 及R²³ 獨立地選自氫、鹵素、氰基、羥基、C_1-6 -烷氧基、鹵基-C_1-6 -烷氧基、C_1-6 -烷基、鹵基-C_1-6 -烷基、羥基-C_1-6 -烷基、(鹵基-C_1-6 -烷基)-羥基-C_1-6 -烷基、C_1-6 -烷氧基羰基-C_1-6 -烷基-、C_1-6 -烷氧基羰基-NH-C_1-6 -烷氧基-、C_1-6 -烷氧基羰基-NH-(C_1-6 -烷氧基)₂ -C_1-6 -烷基-C(O)-NH-C_1-6 -烷氧基-、C_1-6 -烷氧基羰基-NH-C_1-6 -烷氧基-C_1-6 -烷基-C(O)-NH-C_1-6 -烷氧基-、SF₅ 、(C_1-6 -烷基)₃ Si-O-C_1-6 -烷基-、基團

及基團

； R²⁴ 係選自氫、鹵素、羥基、鹵基-C_1-6 -烷基及C_1-6 -烷基； R²⁵ 及R²⁶ 獨立地選自氫、鹵素、C_1-6 -烷基、C_1-6 -烷氧基、鹵基-C_1-6 -烷基、鹵基-C_1-6 -烷氧基、C_1-6 -烷基-SO₂ -及C_3-12 -環烷基； R²⁷ 及R²⁸ 獨立地選自氫、鹵素、C_1-6 -烷氧基、鹵基-C_1-6 -烷氧基、C_1-6 -烷基、鹵基-C_1-6 -烷基、羥基-C_1-6 -烷基、鹵素、羥基、C_1-6 -烷基磺醯基、胺甲醯基、氰基、環烷基-C_1-6 -烷氧基-、C_1-6 -烷基-NH-C(O)-及環烷基； A及B獨立地選自C_6-14 -芳基、C_1-13 -雜芳基、C_3-12 -環烷基及C_2-9 -雜環基； C¹ 係C_3-12 -環烷基或C_2-9 -雜環基； C² 係C_6-14 -芳基； L² 係選自共價鍵、-O-、-CH₂ O-、-CH₂ OCH₂ -及-CH₂ -； L³ 係選自共價鍵、-O-、-CH₂ O-、-OCH₂ -、-CH₂ OCH₂ -及-CH₂ -；且 L^3a 係選自共價鍵、-CH₂ O-、-OCH₂ -、-CH₂ OCH₂ -及-CH₂ -。In one aspect, the invention provides compounds of formula (Ic)

Or a pharmaceutically acceptable salt thereof, wherein: L is selected from -CR ¹ R ² -(CH ₂ ) _p -, -(CH ₂ ) _p -CR ¹ R ² -, -OCR ³ R ⁴ -, -CR ³ R ⁴ O- and covalent bond; m is 0, n is 0 or 1 and X is CR ²⁴ ; or m is 1, n is 1 or 2 and X is CR ²⁴ or N; p is 0, 1 or 2 ; R ¹ is selected from halogen, C _1-6 -alkoxy, C _1-6 -alkyl, halo-C _1-6 -alkyl, hydroxy-C _1-6 -alkyl, C _1-6 -Alkoxy-C _1-6 -alkyl-, halo-C _1-6 -alkoxy, halo-C _1-6 -alkoxy-C _1-6 -alkyl-, cyano and Group

; And R ² is selected from hydrogen, halogen, and hydroxyl; or R ¹ and R ² together with the carbon atom to which they are attached form C _3-12 -cycloalkyl or C _{2-9 -heterocyclic} ; R ³ is selected from C _1-6 -alkyl, halo-C _1-6 -alkyl, C _3-12 -cycloalkyl and C _6-14 -aryl; and R ⁴ is hydrogen; or R ³ and R ⁴ The connected carbon atoms together form C _3-12 -cycloalkyl or C _{2-9 -heterocyclic} ; R ²⁰ is hydrogen or C _1-6 -alkyl; R ²¹ , R ²² and R ^{23 are} independently selected from hydrogen , Halogen, cyano, hydroxy, C _1-6 -alkoxy, halo-C _1-6 -alkoxy, C _1-6 -alkyl, halo-C _1-6 -alkyl, hydroxy- C _1-6 -alkyl, (halo-C _1-6 -alkyl)-hydroxy-C _1-6 -alkyl, C _1-6 -alkoxycarbonyl-C _1-6 -alkyl-, C _1-6 -alkoxycarbonyl-NH-C _{1-6 -alkoxy-} , C _1-6 -alkoxycarbonyl-NH-(C _1-6 -alkoxy) ₂ -C _1-6 - alkyl _{-C (O) -NH-C 1-6} - alkoxy -, C _1-6 - alkoxycarbonyl group -NH-C _1-6 - alkoxy, -C _1-6 - alkyl - C(O)-NH-C _{1-6 -alkoxy-} , SF ₅ , (C _1-6 -alkyl) ₃ Si-OC _1-6 -alkyl-, group

And groups

; R ²⁴ is selected from hydrogen, halogen, hydroxy, halo-C _1-6 -alkyl and C _1-6 -alkyl; R ²⁵ and R ^{26 are} independently selected from hydrogen, halogen, C _1-6 -alkyl Group, C _1-6 -alkoxy, halo-C _1-6 -alkyl, halo-C _1-6 -alkoxy, C _1-6 -alkyl-SO ₂ -and C _3-12 -Cycloalkyl; R ²⁷ and R ^{28 are} independently selected from hydrogen, halogen, C _1-6 -alkoxy, halo-C _1-6 -alkoxy, C _1-6 -alkyl, halo- C _1-6 -alkyl, hydroxy-C _1-6 -alkyl, halogen, hydroxy, C _1-6 -alkylsulfonyl, amine, cyano, cycloalkyl-C _1-6- Alkoxy-, C _1-6 -alkyl-NH-C(O)- and cycloalkyl; A and B are independently selected from C _6-14 -aryl, C _1-13 -heteroaryl, C _3-12 -cycloalkyl and C _{2-9 -heterocyclic} ; C ¹ is C _3-12 -cycloalkyl or C _{2-9 -heterocyclic} ; C ² is C _6-14 -aryl; L ² is selected from covalent bonds, -O-, -CH ₂ O-, -CH ₂ OCH ₂ -and -CH ₂ -; L ³ is selected from covalent bonds, -O-, -CH ₂ O-,- OCH ₂ -, -CH ₂ OCH ₂ -and -CH ₂ -; and L ^3a is selected from covalent bonds, -CH ₂ O-, -OCH ₂ -, -CH ₂ OCH ₂ -and -CH ₂ -.

。In a preferred embodiment, the compound of formula (Ic) is a compound of formula (I) as defined above:

.

其中A、L、X、m、n及R²⁰ 至R²³ 係如技術方案1中所定義。In one embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein the compound of formula (Ic) is a compound of formula (Id):

Wherein A, L, X, m, n and R ²⁰ to R ²³ are as defined in technical solution 1.

其中A、L、X、m、n及R²⁰ 至R²³ 係如技術方案1中所定義。In one embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein the compound of formula (Ic) is a compound of formula (Ie):

Wherein A, L, X, m, n and R ²⁰ to R ²³ are as defined in technical solution 1.

其中A、L、X、m、n及R²⁰ 至R²³ 係如技術方案1中所定義。In one embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein the compound of formula (Ic) is a compound of formula (If):

Wherein A, L, X, m, n and R ²⁰ to R ²³ are as defined in technical solution 1.

其中A、L、X、m、n及R²⁰ 至R²³ 係如技術方案1中所定義。In one embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein the compound of formula (Ic) is a compound of formula (Ig):

Wherein A, L, X, m, n and R ²⁰ to R ²³ are as defined in technical solution 1.

In one embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein: m is 0, n is 0 or 1, and X is CR ²⁴ ; or m is 1, n is 1 and X is CR ²⁴ or N.

In one embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein p is 0 or 1.

In a preferred embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein p is 0.

；且R² 係選自氫、鹵素及羥基；或 R¹ 及R² 與其所連接之碳原子一起形成C_3-12 -環烷基。In one embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein: R ¹ is selected from halogen, C _1-6 -alkoxy, C _1-6 -Alkyl, halo-C _1-6 -alkyl, hydroxy-C _1-6 -alkyl, C _1-6 -alkoxy-C _1-6 -alkyl-, halo-C _1-6 -Alkoxy, halo-C _1-6 -alkoxy-C _1-6 -alkyl-, cyano and groups

; And R ² is selected from hydrogen, halogen, and hydroxyl; or R ¹ and R ² together with the carbon atom to which they are attached form C _3-12 -cycloalkyl.

；且R² 係氫或鹵素。In a preferred embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein R ¹ is selected from halogen, C _1-6 -alkyl, hydroxy-C _{1- 6} -alkyl, C _1-6 -alkoxy-C _1-6 -alkyl-, halo-C _1-6 -alkoxy and groups

; And R ² is hydrogen or halogen.

；且R² 係氫或氟。In a particularly preferred embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein R ¹ is selected from 2-methoxyethyl, methyl, 2,2, 2-trifluoroethoxy, fluorine, 2-hydroxyethyl and groups

; And R ² is hydrogen or fluorine.

In one embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein R ³ is C _1-6 -alkyl or halo-C _1-6 -alkyl ; And R ⁴ is hydrogen.

In a preferred embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein R ³ is C _1-6 -alkyl; and R ⁴ is hydrogen.

In a particularly preferred embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein R ³ is methyl; and R ⁴ is hydrogen.

In a preferred embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein R ²⁰ is hydrogen.

及基團

，其中R²⁷ 、R²⁸ 、C¹ 、C² 、L³ 及L^3a 係如本文所定義。In one embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein R ²¹ is selected from hydrogen, halogen, hydroxyl, C _1-6 -alkoxy, halogen -C _1-6 -alkoxy, C _1-6 -alkyl, halo-C _1-6 -alkyl, hydroxy-C _1-6 -alkyl, (halo-C _1-6 -alkyl Group)-hydroxy-C _1-6 -alkyl, C _1-6 -alkoxycarbonyl-C _1-6 -alkyl-, C _1-6 -alkoxycarbonyl-NH-C _1-6 -alkane Oxy-, C _1-6 -alkoxycarbonyl-NH-(C _1-6 -alkoxy) ₂ -C _1-6 -alkyl-C(O)-NH-C _1-6 -alkoxy group -, C _1-6 - alkoxycarbonyl group -NH-C _1-6 - alkoxy, -C _1-6 - alkyl _{-C (O) -NH-C 1-6} - alkoxy -, SF ₅ , (C _1-6 -alkyl) ₃ Si-OC _1-6 -alkyl-, group

And groups

, Where R ²⁷ , R ²⁸ , C ¹ , C ² , L ³ and L ^3a are as defined herein.

，其中R²⁷ 、R²⁸ 、C¹ 及L³ 係如本文所定義。In a preferred embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein R ²¹ is selected from halogen, C _1-6 -alkoxy, halo-C _1-6 -alkoxy, C _1-6 -alkyl, halo-C _1-6 -alkyl, SF ₅ , C _6-14 -aryl and groups

, Where R ²⁷ , R ²⁸ , C ¹ and L ³ are as defined herein.

，其中R²⁷ 、R²⁸ 、C¹ 及L³ 係如本文所定義。In a particularly preferred embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein R ²¹ is selected from fluorine, chlorine, bromine, methyl, methoxy, third Butyl, propyl, trifluoromethoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1 -Difluoroethyl, SF ₅ , phenyl and groups

, Where R ²⁷ , R ²⁸ , C ¹ and L ³ are as defined herein.

In one embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein R ²² is selected from hydrogen, halogen, C _1-6 -alkoxy, halo- C _1-6 -alkoxy, C _1-6 -alkyl and cyano.

In a preferred embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein R ²² is selected from hydrogen, halogen, C _1-6 -alkoxy and halo -C _1-6 -alkoxy.

In a particularly preferred embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein R ²² is selected from hydrogen, fluorine, chlorine, methoxy, methyl and trifluoro methyl.

In a preferred embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein R ²³ is hydrogen or halogen.

In a particularly preferred embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein R ²³ is hydrogen or fluorine.

In one embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein R ²⁴ is hydrogen.

In one embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein R ²⁵ is selected from hydrogen, halogen, C _1-6 -alkyl, C _1-6 -Alkoxy, halo-C _1-6 -alkyl, halo-C _1-6 -alkoxy, C _1-6 -alkyl-SO ₂ -and C _3-12 -cycloalkyl.

In a preferred embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein R ²⁵ is selected from hydrogen, halogen, C _1-6 -alkoxy and C _{3 -12} -cycloalkyl.

In a particularly preferred embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein R ²⁵ is selected from hydrogen, methoxy, fluorine and cyclopropyl.

In one embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein R ²⁶ is selected from hydrogen, C _1-6 -alkyl and C _1-6 -alkanes Oxy.

In a preferred embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein R ²⁶ is hydrogen or C _1-6 -alkoxy.

In a particularly preferred embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein R ²⁶ is hydrogen or methoxy.

In a preferred embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein R ²⁷ is selected from hydrogen, halo-C _1-6 -alkoxy, C _1-6 -alkyl, halo-C _1-6 -alkyl and halogen.

In a particularly preferred embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein R ²⁷ is selected from methyl, trifluoromethoxy, trifluoromethyl, 2 ,2,2-trifluoro-1-methyl-ethoxy, 2,2,2-trifluoro-1,1-dimethyl-ethoxy, 2,2,2-trifluoroethoxy, Fluorine and chlorine.

In a preferred embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein R ²⁸ is selected from hydrogen, C _1-6 -alkyl and halogen.

In a particularly preferred embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein R ²⁸ is selected from hydrogen, methyl, fluorine and chlorine.

In a preferred embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein A is C _6-14 -aryl or C _1-13 -heteroaryl.

In a particularly preferred embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein A is selected from phenyl, indol-3-yl, 2-pyridyl and 3 -Pyridyl.

In a preferred embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein B is C _6-14 -aryl or C _1-13 -heteroaryl.

In a particularly preferred embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein B is phenyl or 1,2,4-oxadiazol-5-yl.

In one embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein C ¹ is selected from azetidine-1-yl, pyrrolidin-1-yl, Cyclopropyl and oxetan-3-yl.

In one embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein C ² is phenyl.

In a preferred embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein L is selected from -CR ¹ R ² -(CH ₂ ) _p -, -OCR ³ R ⁴ -, -CR ³ R ⁴ O- and covalent bonds; wherein R ¹ to R ⁴ and p are as defined herein.

In one embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein L ² is selected from covalent bonds, —O— and —CH ₂ —.

In a preferred embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein L ² is a covalent bond.

In one embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein L ³ is selected from a covalent bond, -CH ₂ O-, and -CH ₂ -.

In a preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein L ³ is a covalent bond or -CH ₂ -.

In one embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein L ^3a is a covalent bond or -CH ₂ -.

In a preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein L ^3a is a covalent bond.

；且R² 係選自氫、鹵素及羥基；或 R¹ 及R² 與其所連接之碳原子一起形成C_3-12 -環烷基； R³ 係C_1-6 -烷基或鹵基-C_1-6 -烷基； R²⁰ 係氫或C_1-6 -烷基； R²¹ 係選自氫、鹵素、羥基、C_1-6 -烷氧基、鹵基-C_1-6 -烷氧基、C_1-6 -烷基、鹵基-C_1-6 -烷基、羥基-C_1-6 -烷基、(鹵基-C_1-6 -烷基)-羥基-C_1-6 -烷基、C_1-6 -烷氧基羰基-C_1-6 -烷基-、C_1-6 -烷氧基羰基-NH-C_1-6 -烷氧基-、SF₅ 、(C_1-6 -烷基)₃ Si-O-C_1-6 -烷基-、基團

及基團

； R²² 係選自氫、鹵素、C_1-6 -烷氧基、鹵基-C_1-6 -烷氧基、C_1-6 -烷基及氰基； R²³ 係氫或鹵素； R²⁴ 係選自氫、鹵素、羥基及C_1-6 -烷基； R²⁵ 係選自氫、鹵素、C_1-6 -烷基、C_1-6 -烷氧基、鹵基-C_1-6 -烷基、鹵基-C_1-6 -烷氧基、C_1-6 -烷基-SO₂ -及C_3-12 -環烷基； R²⁶ 係選自氫、C_1-6 -烷基及C_1-6 -烷氧基； R²⁷ 係選自氫、鹵素、C_1-6 -烷氧基、鹵基-C_1-6 -烷氧基、C_1-6 -烷基、鹵基-C_1-6 -烷基、羥基-C_1-6 -烷基、鹵素、羥基、C_1-6 -烷基磺醯基、胺甲醯基、氰基、環烷基-C_1-6 -烷氧基-及環烷基； R²⁸ 係選自氫、C_1-6 -烷基及鹵素； A 係C_6-14 -芳基或C_1-13 -雜芳基； B 係C_6-14 -芳基或C_1-13 -雜芳基； C¹ 係C_3-12 -環烷基或C_2-9 -雜環基； C² 係C_6-14 -芳基； L² 係選自共價鍵、-O-及-CH₂ -； L³ 係選自共價鍵、-CH₂ O-及-CH₂ -；且 L^3a 係共價鍵或-CH₂ -。In one embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein: m is 0, n is 0 or 1, and X is CR ²⁴ ; or m is 1, n is 1 and X is CR ²⁴ or N; L is selected from -CR ¹ R ² -(CH ₂ ) _p -, -OCHR ³ -, -CHR ³ O- and covalent bonds; p is 0 or 1; R ¹ is selected from halogen, C _1-6 -alkoxy, C _1-6 -alkyl, halo-C _1-6 -alkyl, hydroxy-C _1-6 -alkyl, C _1-6 -alkane Oxy-C _1-6 -alkyl-, halo-C _1-6 -alkoxy, halo-C _1-6 -alkoxy-C _1-6 -alkyl-, cyano and groups

; And R ² is selected from hydrogen, halogen, and hydroxyl; or R ¹ and R ² together with the carbon atom to which they are attached form C _3-12 -cycloalkyl; R ³ is C _1-6 -alkyl or halo- C _1-6 -alkyl; R ²⁰ is hydrogen or C _1-6 -alkyl; R ²¹ is selected from hydrogen, halogen, hydroxy, C _1-6 -alkoxy, halo-C _1-6 -alkyl Oxygen, C _1-6 -alkyl, halo-C _1-6 -alkyl, hydroxy-C _1-6 -alkyl, (halo-C _1-6 -alkyl)-hydroxy-C _{1- 6} -alkyl, C _1-6 -alkoxycarbonyl-C _1-6 -alkyl-, C _1-6 -alkoxycarbonyl-NH-C _{1-6 -alkoxy-} , SF ₅ , ( C _1-6 -alkyl) ₃ Si-OC _1-6 -alkyl-, group

And groups

; R ²² is selected from hydrogen, halogen, C _1-6 -alkoxy, halo-C _1-6 -alkoxy, C _1-6 -alkyl and cyano; R ²³ is hydrogen or halogen; R ²⁴ is selected from hydrogen, halogen, hydroxy and C _1-6 -alkyl; R ²⁵ is selected from hydrogen, halogen, C _1-6 -alkyl, C _1-6 -alkoxy, halo-C _{1- 6} -alkyl, halo-C _1-6 -alkoxy, C _1-6 -alkyl-SO ₂ -and C _3-12 -cycloalkyl; R ²⁶ is selected from hydrogen, C _1-6- Alkyl and C _1-6 -alkoxy; R ²⁷ is selected from hydrogen, halogen, C _1-6 -alkoxy, halo-C _1-6 -alkoxy, C _1-6 -alkyl, halo -C _1-6 - alkyl, hydroxy -C _1-6 - alkyl, halogen, hydroxy, C _1-6 - alkyl sulfonic acyl, acyl carbamoyl, cyano, cycloalkyl -C _{1 -6 -alkoxy-} and cycloalkyl; R ²⁸ is selected from hydrogen, C _1-6 -alkyl and halogen; A is C _6-14 -aryl or C _1-13 -heteroaryl; B is C _6-14 -aryl or C _1-13 -heteroaryl; C ¹ is C _3-12 -cycloalkyl or C _{2-9 -heterocyclic} ; C ² is C _6-14 -aryl; L ² is selected from covalent bonds, -O- and -CH ₂ -; L ³ is selected from covalent bonds, -CH ₂ O- and -CH ₂ -; and L ^3a is a covalent bond or -CH ₂ -.

； R² 係氫或鹵素； R³ 係C_1-6 -烷基； R²⁰ 係氫； R²¹ 係選自鹵素、C_1-6 -烷氧基、鹵基-C_1-6 -烷氧基、C_1-6 -烷基、鹵基-C_1-6 -烷基、SF₅ 、C_6-14 -芳基及基團

； R²² 係選自氫、鹵素、C_1-6 -烷氧基及鹵基-C_1-6 -烷氧基； R²³ 係氫或鹵素； R²⁵ 係選自氫、鹵素、C_1-6 -烷氧基及C_3-12 -環烷基； R²⁶ 係氫或C_1-6 -烷氧基； R²⁷ 係選自氫、鹵基-C_1-6 -烷氧基、C_1-6 -烷基、鹵基-C_1-6 -烷基及鹵素； R²⁸ 係選自氫、C_1-6 -烷基及鹵素； A 係C_6-14 -芳基或C_1-13 -雜芳基； B 係C_6-14 -芳基或C_1-13 -雜芳基； C¹ 係C_3-12 -環烷基或C_2-9 -雜環基； L³ 係共價鍵或-CH₂ -。In a preferred embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein: m is 0, n is 0 or 1, and X is CH; or m is 1, n is 1 and X is CH or N; L is selected from -CR ¹ R ² -, -OCHR ³ -, -CHR ³ O- and covalent bonds; R ¹ is selected from halogen, C _1-6 -alkyl , Hydroxy-C _1-6 -alkyl, C _1-6 -alkoxy-C _1-6 -alkyl-, halo-C _1-6 -alkoxy and groups

; R ² is hydrogen or halogen; R ³ is C _1-6 -alkyl; R ²⁰ is hydrogen; R ²¹ is selected from halogen, C _1-6 -alkoxy, halo-C _1-6 -alkoxy Group, C _1-6 -alkyl, halo-C _1-6 -alkyl, SF ₅ , C _6-14 -aryl and group

; R ²² is selected from hydrogen, halogen, C _1-6 -alkoxy and halo-C _1-6 -alkoxy; R ²³ is hydrogen or halogen; R ²⁵ is selected from hydrogen, halogen, C _{1- 6} -alkoxy and C _3-12 -cycloalkyl; R ²⁶ is hydrogen or C _1-6 -alkoxy; R ²⁷ is selected from hydrogen, halo-C _1-6 -alkoxy, C _{1 -6} -alkyl, halo-C _1-6 -alkyl and halogen; R ²⁸ is selected from hydrogen, C _1-6 -alkyl and halogen; A is C _6-14 -aryl or C _1-13 -Heteroaryl; B is C _6-14 -aryl or C _1-13 -heteroaryl; C ¹ is C _3-12 -cycloalkyl or C _{2-9 -heterocyclic} ; L ³ is covalent Key or -CH ₂ -.

； R² 係氫或氟； R³ 係甲基； R²⁰ 係氫； R²¹ 係選自氟、氯、溴、甲基、甲氧基、第三丁基、丙基、三氟甲氧基、2-氟乙氧基、2,2,2-三氟乙氧基、三氟甲基、2,2,2-三氟乙基、1,1-二氟乙基、SF₅ 、苯基及基團

； R²² 係選自氫、氟、氯、甲氧基、甲基及三氟甲基； R²³ 係氫或氟； R²⁵ 係選自氫、甲氧基、氟及環丙基； R²⁶ 係氫或甲氧基； R²⁷ 係選自甲基、三氟甲氧基、三氟甲基、2,2,2-三氟-1-甲基-乙氧基、2,2,2-三氟-1,1-二甲基-乙氧基、2,2,2-三氟乙氧基、氟及氯； R²⁸ 係選自氫、甲基、氟及氯； A 係選自苯基、吲哚-3-基、2-吡啶基及3-吡啶基； B 係苯基或1,2,4-噁二唑-5-基； C¹ 係選自氮雜環丁-1-基、吡咯啶-1-基、環丙基及氧雜環丁-3-基；且 L³ 係共價鍵或-CH₂ -。In a particularly preferred embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein: m is 0, n is 0 or 1, and X is CH; or m is 1, n is 1 and X is CH or N; L is selected from -CR ¹ R ² -, -OCHR ³ -, -CHR ³ O- and covalent bonds; R ¹ is selected from 2-methoxyethyl, methyl Radicals, 2,2,2-trifluoroethoxy, fluorine, 2-hydroxyethyl and radicals

; R ² is hydrogen or fluorine; R ³ is methyl; R ²⁰ is hydrogen; R ²¹ is selected from fluorine, chlorine, bromine, methyl, methoxy, third butyl, propyl, trifluoromethoxy , 2-fluoroethoxy, 2,2,2-trifluoroethoxy, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, SF ₅ , phenyl And groups

; R ²² is selected from hydrogen, fluorine, chlorine, methoxy, methyl and trifluoromethyl; R ²³ is hydrogen or fluorine; R ²⁵ is selected from hydrogen, methoxy, fluorine and cyclopropyl; R ²⁶ Is hydrogen or methoxy; R ²⁷ is selected from methyl, trifluoromethoxy, trifluoromethyl, 2,2,2-trifluoro-1-methyl-ethoxy, 2,2,2- Trifluoro-1,1-dimethyl-ethoxy, 2,2,2-trifluoroethoxy, fluorine and chlorine; R ²⁸ is selected from hydrogen, methyl, fluorine and chlorine; A is selected from benzene Group, indol-3-yl, 2-pyridyl and 3-pyridyl; B is phenyl or 1,2,4-oxadiazol-5-yl; C ¹ is selected from azetidine-1- Group, pyrrolidin-1-yl, cyclopropyl and oxetan-3-yl; and L ³ is a covalent bond or -CH ₂ -.

In one embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein: m is 0, n is 0 or 1, and X is CR ²⁴ ; or m is 1, n is 1 and X is CR ²⁴ or N; and R ²⁴ is selected from hydrogen, halogen, hydroxyl and C _1-6 -alkyl.

In a preferred embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein: m is 0, n is 0 or 1, and X is CH; or m is 1, n is 1, and X is CH or N.

；且R² 係選自氫、鹵素及羥基；或 R¹ 及R² 與其所連接之碳原子一起形成C_3-12 -環烷基； R³ 係C_1-6 -烷基或鹵基-C_1-6 -烷基； R²⁵ 係選自氫、鹵素、C_1-6 -烷基、C_1-6 -烷氧基、鹵基-C_1-6 -烷基、鹵基-C_1-6 -烷氧基、C_1-6 -烷基-SO₂ -及C_3-12 -環烷基； R²⁶ 係選自氫、C_1-6 -烷基及C_1-6 -烷氧基； B 係C_{6- 14} -芳基或C_1-13 -雜芳基；且 L² 係選自共價鍵、-O-及-CH₂ -。In one embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein: L is selected from -CR ¹ R ² -(CH ₂ ) _p -, -OCHR ³ -, -CHR ³ O- and covalent bond; p is 0 or 1; R ¹ is selected from halogen, C _1-6 -alkoxy, C _1-6 -alkyl, halo-C _1-6- Alkyl, hydroxy-C _1-6 -alkyl, C _1-6 -alkoxy-C _1-6 -alkyl-, halo-C _1-6 -alkoxy, halo-C _1-6 -Alkoxy-C _1-6 -alkyl-, cyano and groups

; And R ² is selected from hydrogen, halogen, and hydroxyl; or R ¹ and R ² together with the carbon atom to which they are attached form C _3-12 -cycloalkyl; R ³ is C _1-6 -alkyl or halo- C _1-6 -alkyl; R ²⁵ is selected from hydrogen, halogen, C _1-6 -alkyl, C _1-6 -alkoxy, halo-C _1-6 -alkyl, halo-C _{1 -6} -alkoxy, C _1-6 -alkyl-SO ₂ -and C _3-12 -cycloalkyl; R ²⁶ is selected from hydrogen, C _1-6 -alkyl and C _1-6 -alkoxy group; B-based C _{6- 14} - aryl or C _1-13 - heteroaryl; and L ² is selected from a covalent bond, -O- and -CH ₂ -.

； R² 係氫或鹵素； R³ 係C_1-6 -烷基； R²⁵ 係選自氫、鹵素、C_1-6 -烷氧基及C_3-12 -環烷基； R²⁶ 係氫或C_1-6 -烷氧基；且 B 係C_6-14 -芳基或C_1-13 -雜芳基。In a preferred embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein: L is selected from -CR ¹ R ² -, -OCHR ³ -, -CHR ³ O- and covalent bond; R ¹ is selected from halogen, C _1-6 -alkyl, hydroxy-C _1-6 -alkyl, C _1-6 -alkoxy-C _1-6 -alkyl-, Halo-C _1-6 -alkoxy and groups

; R ² is hydrogen or halogen; R ³ is C _1-6 -alkyl; R ²⁵ is selected from hydrogen, halogen, C _1-6 -alkoxy and C _3-12 -cycloalkyl; R ²⁶ is hydrogen Or C _1-6 -alkoxy; and B is C _6-14 -aryl or C _1-13 -heteroaryl.

； R² 係氫或氟； R³ 係甲基； R²⁵ 係選自氫、甲氧基、氟及環丙基； R²⁶ 係氫或甲氧基；且 B 係苯基或1,2,4-噁二唑-5-基。In a particularly preferred embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein: L is selected from -CR ¹ R ² -, -OCHR ³ -, -CHR ³ O- and covalent bond; R ¹ is selected from 2-methoxyethyl, methyl, 2,2,2-trifluoroethoxy, fluorine, 2-hydroxyethyl and groups

; R ² is hydrogen or fluorine; R ³ is methyl; R ²⁵ is selected from hydrogen, methoxy, fluorine and cyclopropyl; R ²⁶ is hydrogen or methoxy; and B is phenyl or 1,2, 4-oxadiazol-5-yl.

及基團

； R²² 係選自氫、鹵素、C_1-6 -烷氧基、鹵基-C_1-6 -烷氧基、C_1-6 -烷基及氰基； R²³ 係氫或鹵素； R²⁷ 係選自氫、鹵素、C_1-6 -烷氧基、鹵基-C_1-6 -烷氧基、C_1-6 -烷基、鹵基-C_1-6 -烷基、羥基-C_1-6 -烷基、鹵素、羥基、C_1-6 -烷基磺醯基、胺甲醯基、氰基、環烷基-C_1-6 -烷氧基-及環烷基； R²⁸ 係選自氫、C_1-6 -烷基及鹵素； A 係C_6-14 -芳基或C_1-13 -雜芳基； C¹ 係C_3-12 -環烷基或C_2-9 -雜環基； C² 係C_6-14 -芳基； L³ 係選自共價鍵、-CH₂ O-及-CH₂ -；且 L^3a 係共價鍵或-CH₂ -。In one embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein: R ²¹ is selected from hydrogen, halogen, hydroxyl, C _1-6 -alkoxy, Halo-C _1-6 -alkoxy, C _1-6 -alkyl, halo-C _1-6 -alkyl, hydroxy-C _1-6 -alkyl, (halo-C _1-6- Alkyl)-hydroxy-C _1-6 -alkyl, C _1-6 -alkoxycarbonyl-C _1-6 -alkyl-, C _1-6 -alkoxycarbonyl-NH-C _1-6- Alkoxy-, SF ₅ , (C _1-6 -alkyl) ₃ Si-OC _1-6 -alkyl-, group

And groups

; R ²² is selected from hydrogen, halogen, C _1-6 -alkoxy, halo-C _1-6 -alkoxy, C _1-6 -alkyl and cyano; R ²³ is hydrogen or halogen; R ²⁷ is selected from hydrogen, halogen, C _1-6 -alkoxy, halo-C _1-6 -alkoxy, C _1-6 -alkyl, halo-C _1-6 -alkyl, hydroxy- C _1-6 -alkyl, halogen, hydroxyl, C _1-6 -alkylsulfonyl, amine, cyano, cycloalkyl-C _{1-6 -alkoxy-} and cycloalkyl; R ²⁸ is selected from hydrogen, C _1-6 -alkyl and halogen; A is C _6-14 -aryl or C _1-13 -heteroaryl; C ¹ is C _3-12 -cycloalkyl or C _{2- 9} -heterocyclic group; C ² is C _6-14 -aryl; L ³ is selected from covalent bond, -CH ₂ O- and -CH ₂ -; and L ^3a is covalent bond or -CH ₂ -.

； R²² 係選自氫、鹵素、C_1-6 -烷氧基及鹵基-C_1-6 -烷氧基； R²³ 係氫或鹵素； R²⁷ 係選自氫、鹵基-C_1-6 -烷氧基、C_1-6 -烷基、鹵基-C_1-6 -烷基及鹵素； R²⁸ 係選自氫、C_1-6 -烷基及鹵素； A 係C_6-14 -芳基或C_1-13 -雜芳基； C¹ 係C_3-12 -環烷基或C_2-9 -雜環基；且 L³ 係共價鍵或-CH₂ -。In a preferred embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein: R ²¹ is selected from halogen, C _1-6 -alkoxy, halo- C _1-6 -alkoxy, C _1-6 -alkyl, halo-C _1-6 -alkyl, SF ₅ , C _6-14 -aryl and groups

; R ²² is selected from hydrogen, halogen, C _1-6 -alkoxy and halo-C _1-6 -alkoxy; R ²³ is hydrogen or halogen; R ²⁷ is selected from hydrogen, halo-C _{1 -6} -alkoxy, C _1-6 -alkyl, halo-C _1-6 -alkyl and halogen; R ²⁸ is selected from hydrogen, C _1-6 -alkyl and halogen; A is C _{6- 14} -aryl or C _1-13 -heteroaryl; C ¹ is C _3-12 -cycloalkyl or C _{2-9 -heterocyclic} ; and L ³ is a covalent bond or -CH ₂ -.

； R²² 係選自氫、氟、氯、甲氧基、甲基及三氟甲基； R²³ 係氫或氟； R²⁷ 係選自甲基、三氟甲氧基、三氟甲基、2,2,2-三氟-1-甲基-乙氧基、2,2,2-三氟-1,1-二甲基-乙氧基、2,2,2-三氟乙氧基、氟及氯； R²⁸ 係選自氫、甲基、氟及氯； A 係選自苯基、吲哚-3-基、2-吡啶基及3-吡啶基； C¹ 係選自氮雜環丁-1-基、吡咯啶-1-基、環丙基及氧雜環丁-3-基；且 L³ 係共價鍵或-CH₂ -。In a particularly preferred embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein: R ²¹ is selected from fluorine, chlorine, bromine, methyl, methoxy, Tributyl, propyl, trifluoromethoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, trifluoromethyl, 2,2,2-trifluoroethyl, 1, 1-difluoroethyl, SF ₅ , phenyl and groups

; R ²² is selected from hydrogen, fluorine, chlorine, methoxy, methyl and trifluoromethyl; R ²³ is hydrogen or fluorine; R ²⁷ is selected from methyl, trifluoromethoxy, trifluoromethyl, 2,2,2-trifluoro-1-methyl-ethoxy, 2,2,2-trifluoro-1,1-dimethyl-ethoxy, 2,2,2-trifluoroethoxy , Fluorine and chlorine; R ²⁸ is selected from hydrogen, methyl, fluorine and chlorine; A is selected from phenyl, indol-3-yl, 2-pyridyl and 3-pyridyl; C ¹ is selected from aza Cyclobut-1-yl, pyrrolidin-1-yl, cyclopropyl and oxetan-3-yl; and L ³ is a covalent bond or -CH ₂ -.

In one embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as set forth herein, which is selected from the compounds presented in Table 1 and Table 3.

In a preferred embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as set forth herein, which is selected from the compounds presented in Table 1.

In a particularly preferred embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof as described herein, wherein the compound of formula (Ic) is selected from: Racemic-cis-6-(4-(5-chloro-1-(cyclopropylmethyl)-1H-indol-3-yl)hexahydropyridine-1-carbonyl)hexahydro-2H-pyridine And [4,3-b][1,4]oxazin-3(4H)-one; Racemic-cis-6-(4-(5-chloro-1-methyl-1H-indol-3-yl)hexahydropyridine-1-carbonyl)hexahydro-2H-pyrido[4,3 -b][1,4]oxazin-3(4H)-one; Racemic-cis-6-(4-(1-(4-fluorophenyl)-3-methoxypropyl)hexahydropyridine-1-carbonyl)hexahydro-2H-pyrido[4,3 -b][1,4]oxazin-3(4H)-one; Racemic-cis-6-(4-((4-chlorophenyl)(phenyl)methyl)hexahydropyrazine-1-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4]oxazine-3(4H)-one; (+)-cis-6-(4-(bis(4-fluorophenyl)methyl)hexahydropyrazine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1, 4] Oxazine-3(4H)-one; (+)- or (-)-cis-6-(4-(5-chloro-1-cyclopropyl-1H-indol-3-yl)hexahydropyridine-1-carbonyl)hexahydro-2H- Pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (-)-cis-6-(4-(5-chloro-1-(oxetan-3-yl)-1H-indol-3-yl)hexahydropyridine-1- Carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; Racemic-cis-6-(4-(1-(4-fluorophenyl)-3-hydroxypropyl)hexahydropyridine-1-carbonyl)hexahydro-2H-pyrido[4,3-b ][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-(difluoro(4-(trifluoromethyl)phenyl)methyl)hexahydropyridine-1-carbonyl)hexahydro-2H-pyrido(4,3-b ][1,4]oxazin-3(4H)-one; (+) or (-)-cis-6-(4-((R or S)-1-(2-chloro-4-fluorophenoxy)ethyl)hexahydropyridine-1-carbonyl)hexahydro -2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+) or (-)-cis-6-(4-((4-chlorophenyl)difluoromethyl)hexahydropyridine-1-carbonyl)hexahydro-2H-pyrido[4,3-b ][1,4]oxazin-3(4H)-one; (+) or (-)-cis-6-(4-((2-chloro-4-fluorophenyl)difluoromethyl)hexahydropyridine-1-carbonyl)hexahydro-2H-pyrido[4 ,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((R or S)-1-(4-(trifluoromethyl)phenyl)ethyl)hexahydropyridine-1-carbonyl)hexahydro-2H-pyrido [4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((S or R)-(4-fluorophenyl)(2,2,2-trifluoroethoxy)methyl)hexahydropyridine-1-carbonyl)hexa Hydrogen-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-[4-[(S or R)-(4-fluorophenyl)-(3-methoxyphenyl)methyl]hexahydropyridine-1-carbonyl]-4,4a ,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-(4-((R or S)-(4-fluorophenyl)(3-methoxyphenyl)methyl)hexahydropyridine-1-carbonyl)hexahydro-2H- Pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((S or R)-(3-(2-fluoroethoxy)phenyl)(phenyl)methyl)hexahydropyridine-1-carbonyl)hexahydro- 2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((3-cyclopropyl-1,2,4-oxadiazol-5-yl)(4-fluorophenyl)methyl)hexahydropyridine-1-carbonyl ) Hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((S or R)-(4-fluorophenyl)(4-methoxyphenyl)methyl)hexahydropyridine-1-carbonyl)hexahydro-2H- Pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((S or R)-(3,4-dimethoxyphenyl)(4-fluorophenyl)methyl)hexahydropyridine-1-carbonyl)hexahydro -2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((R or S)-(4-fluorophenyl)(4-methoxyphenyl)methyl)hexahydropyridine-1-carbonyl)hexahydro-2H- Pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((S or R)-(4-(2-fluoroethoxy)phenyl)(4-fluorophenyl)methyl)hexahydropyridine-1-carbonyl) Hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-[3-[4-(trifluoromethoxy)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyridine And [4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-(3-(2'-trifluoromethoxy)-[1,1'-biphenyl]-4-yl)azetidine-1-carbonyl)hexahydro-2H -Pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(2'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-1-carbonyl)hexahydro-2H -Pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(2',4'-difluoro-[1,1'-biphenyl]-4-yl)azetidine-1-carbonyl)hexahydro-2H- Pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-(3-(trifluoromethyl)azetidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H- Pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-Bromo-3-chlorophenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4 ] Oxazin-3(4H)-one; (4aR,8aS)-6-[3-[4-(4-chloro-2-fluoro-phenyl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8, 8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(2-chloro-4-fluoro-phenyl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8, 8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-(3-(4-(3-((1,1,1-trifluoropropan-2-yl)oxy)azetidin-1-yl)phenyl)aza Cyclobutane-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-(T-butyl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1, 4] Oxazine-3(4H)-one; (4aR,8aS)-6-(3-(4-(trifluoromethyl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1, 4] Oxazine-3(4H)-one; (4aR,8aS)-6-(3-(4-(3-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)azetidin-1-yl) Phenyl) azetidine-1-carbonyl) hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-(1,1-difluoroethyl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido(4,3-b ][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-(3,3-dimethylpyrrolidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[ 4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-(3-(trifluoromethoxy)azetidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H -Pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(6-(2,4-dichlorophenyl)pyridin-3-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido(4, 3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-[3-[4-(2,2,2-trifluoroethoxy)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8 ,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[3-[(1S or 1R)-2,2,2-trifluoro-1-methyl-ethoxy]azetidin-1-yl ]Phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[3-[(1R or 1S)-2,2,2-trifluoro-1-methyl-ethoxy]azetidin-1-yl ]Phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-(3-(4-(2-(trifluoromethyl)pyrrolidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido [4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-(3-(trifluoromethyl)pyrrolidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido [4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-(3-(2,2,2-trifluoroethoxy)azetidin-1-yl)phenyl)azetidine-1- Carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(6-(2-(trifluoromethyl)pyrrolidin-1-yl)pyridin-3-yl)azetidine-1-carbonyl)hexahydro-2H -Pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-(pentafluoro-l6-thio)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4]oxazine-3(4H)-one; (4aR,8aS)-6-(3-(2-fluoro-4-(trifluoromethoxy)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3- b][1,4]oxazine-3(4H)-one; (4aR,8aS)-6-[3-[4-(2,2,2-trifluoroethyl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8, 8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[1-(trifluoromethyl)cyclopropyl]phenyl]azetidine-1-carbonyl]-4,4a,5,7,8 ,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(6,6-difluoro-2-azaspiro[3.3]hept-2-yl)phenyl]azetidine-1-carbonyl]- 4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-(3-(5-(2,4-dichlorophenyl)pyridin-2-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido(4, 3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-((R or S)-2-(trifluoromethyl)pyrrolidin-1-yl)phenyl)azetidine-1-carbonyl)hexa Hydrogen-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-((S or R)-2-(trifluoromethyl)pyrrolidin-1-yl)phenyl)azetidine-1-carbonyl)hexa Hydrogen-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-((R or S)-3-(trifluoromethyl)pyrrolidin-1-yl)phenyl)azetidine-1-carbonyl)hexa Hydrogen-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-((S or R)-3-(trifluoromethyl)pyrrolidin-1-yl)phenyl)azetidine-1-carbonyl)hexa Hydrogen-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido(4,3- b][1,4]oxazine-3(4H)-one; (4aR,8aS)-6-(3-(3-methyl-4-(trifluoromethoxy)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido(4,3 -b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(3,5-difluoro-4-(trifluoromethoxy)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido(4 ,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(3-chloro-4-(trifluoromethoxy)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3- b][1,4]oxazine-3(4H)-one; (4aR,8aS)-6-((R or S)-3-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)pyrrolidin-1-carbonyl)hexahydro- 2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-((S or R)-3-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)pyrrolidin-1-carbonyl)hexahydro- 2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-(T-butyl)-3-methoxyphenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido(4,3 -b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-propylphenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine -3(4H)-one; (4aR,8aS)-6-(3-(4-(trifluoromethoxy)-3-(trifluoromethyl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido [4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(5-(((R or S)-3-(trifluoromethyl)pyrrolidin-1-yl)pyridin-2-yl)azetidine-1- Carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(5-((S or R)-3-(trifluoromethyl)pyrrolidin-1-yl)pyridin-2-yl)azetidine-1- Carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-[3-[6-[3-(R or S)-(trifluoromethyl)pyrrolidin-1-yl]-3-pyridyl]azetidine-1- Carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[6-[3-(S or R)-(trifluoromethyl)pyrrolidin-1-yl]-3-pyridyl]azetidine-1- Carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-(4-tetrahydropyran-3-ylphenyl)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydro Pyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[2-methoxy-4-(2,2,2-trifluoroethyl)phenyl]azetidine-1-carbonyl]-4,4a, 5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; and (4aR,8aS)-6-(3-(4-(neopentyloxy)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazine-3(4H)-one.

In one embodiment, the present invention provides a pharmaceutically acceptable salt or ester of a compound of formula (I) as set forth herein. In certain embodiments, the present invention provides pharmaceutically acceptable salts, especially hydrochlorides, of compounds of formula (I) as set forth herein. In another specific embodiment, the present invention provides a pharmaceutically acceptable ester of a compound of formula (I) as set forth herein. In another specific embodiment, the present invention provides compounds of formula (I) as set forth herein.

Manufacturing Process The preparation of the compound of formula (I) of the present invention can be carried out continuously or by combining synthetic routes. The synthesis of the present invention is shown in the following general scheme. The skills required to carry out the reaction and purification of the resulting product are known to those skilled in the art. Unless indicated to the contrary, the substituents and superscripts used in the following process description have the meanings given herein.

If one of the starting materials, intermediates or compounds of formula (I) contains one or more functional groups that are unstable or reactive under the reaction conditions of one or more reaction steps, they can be applied before the critical step Methods well known in the industry introduce suitable protecting groups (such as, for example, TW Greene and PGM Wutts, "Protective Groups in Organic Chemistry", 5th Edition, 2014, John Wiley & Sons NY). These protecting groups can be removed later in the synthesis using standard methods described in the literature.

If the starting material or intermediate contains a stereogenic center, the compound of formula (I) can be obtained as a diastereomer or a mixture of mirror isomers, which can be separated by methods well known in the industry, such as chiral HPLC, Chiral SFC or chiral crystal. The racemic compound can be separated into its mirror image, for example, by crystallizing with an optically pure acid through a non-mirromeric isomer salt or by a specific chromatographic method using a chiral adsorbent or chiral eluent to separate the mirror image body. Similarly, starting materials and intermediates containing stereogenic centers can be separated to obtain non-mirror/mirror-enriched starting materials and intermediates. The use of these starting materials and intermediates for non-mirromeric/mirromeric enrichment in the synthesis of compounds of formula (I) will generally produce separate non-mirromeric/mirromeric enriched compounds of formula (I) .

Those skilled in the art will recognize that in the synthesis of compounds of formula (I), unless undesired, an "orthogonal protecting group strategy" will be applied, which allows the cleavage of several protecting groups one at a time without affecting Other protecting groups in the molecule. The principle of orthogonal protection is well known in the industry and has also been described in the literature (eg Barany and RB Merrifield, J. Am. Chem. Soc. 1977 , 99 , 7363; H. Waldmann et al., Angew. Chem. Int. Ed Engl. 1996 , 35 , 2056).

Those skilled in the art will recognize that the reaction sequence can vary depending on the reactivity and nature of the intermediate.

In more detail, the compound of formula (I) can be produced by the method given below, by the method given in the examples, or by a similar method. Appropriate reaction conditions for individual reaction steps are known to those skilled in the art. In addition, for the reaction conditions described in the literature that affect the reaction, see (for example): Comprehensive Organic Transformations: A Guide to Functional Group Preparations , 2nd Edition , Richard C. Larock. John Wiley & Sons, New York, NY. 1999 . It has been found that the reaction can be carried out conveniently in the presence or absence of a solvent. There is no specific limit to the nature of the solvent to be used, provided that it has no deleterious effect on the reaction or reagent involved and that it can dissolve the reagent at least to some extent. The reaction can be carried out in a wide temperature range, and the precise reaction temperature is not critical to the present invention. The reaction is conveniently carried out in a temperature range between -78°C and reflux. The time required for the reaction can also vary widely depending on many factors, especially the reaction temperature and the nature of the reagents. However, a period of 0.5 hours to several days will usually be sufficient to produce the intermediates and compounds. The reaction sequence is not limited to those shown in the scheme, however, depending on the starting materials and their respective reactivity, the sequence of reaction steps can be freely changed.

If starting materials or intermediates are not commercially available or their synthesis is not described in the literature, they can be prepared similar to existing analogue procedures or as outlined in the experimental section.

。The following abbreviations are used in this article: AcOH=acetic acid, ACN=acetonitrile, Boc=third butyloxycarbonyl, CAS RN=Chemical Abstracts Registration Number, Cbz=benzyloxycarbonyl, Cs ₂ CO ₃ =cesium carbonate, CO = Carbon monoxide, CuCl=copper(I) chloride, CuCN=copper(I) cyanide, CuI=copper(I) iodide, DMAP=4-dimethylaminopyridine, DME=dimethoxyethane, DMEDA = N,N'-dimethylethylenediamine, DMF = N,N-dimethylformamide, DIPEA = N,N-diisopropylethylamine, dppf = 1,1 bis(diphenyl Phosphino)ferrocene, EDC.HCl = N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, EI = electron collision, ESI = electrospray ionization, EtOAc = ethyl acetate, EtOH = ethanol, h = hour, FA = formic acid, H ₂ O = water, H ₂ SO ₄ = sulfuric acid, Hal = halogen, HATU = hexafluorophosphate 1-[bis(dimethylamino )Methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide, HBTU = hexafluorophosphate O-benzotriazole-N,N,N' , N'-Tetramethyl-ureium, HCl = hydrochloric acid, HOBt = 1-hydroxy-1H-benzotriazole; HPLC = high performance liquid chromatography, iPrMgCl = isopropyl magnesium chloride, I ₂ = iodine, IPA = 2-propanol, (Ir[dF(CF ₃ )ppy] ₂ (dtbpy))PF ₆ = hexafluorophosphate [4,4′-bis(1,1-dimethylethyl)-2,2′- Bipyridine-N1,N1′]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl-N]phenyl-C]iridium(III), ISP=positive ion Spray (mode), ISN = negative ion spray (mode), K ₂ CO ₃ = potassium carbonate, KHCO ₃ = potassium bicarbonate, KI = potassium iodide, KOH = potassium hydroxide, K ₃ PO ₄ = potassium phosphate, LiAlH ₄ or LAH = lithium aluminum hydride, LiHMDS = lithium bis(trimethylsilyl)amine, LiOH = lithium hydroxide, MgSO ₄ = magnesium sulfate, min = minutes, mL = milliliters, MPLC = medium pressure liquid chromatography, MS = Mass spectrometry, NaH = sodium hydride, NaHCO ₃ = sodium bicarbonate, NaNO ₂ = sodium nitrite, NaOH = sodium hydroxide, Na ₂ CO ₃ = sodium carbonate, Na ₂ SO ₄ = sodium sulfate, Na ₂ S ₂ O ₃ = Sodium thiosulfate, NBS = N-bromosuccinimide, nBuLi = n-butyllithium, NEt ₃ = triethylamine (TEA), NH ₄ Cl = ammonium chloride, NiCl ₂ glyme = nickel chloride (II ) Ethylene glycol dimethyl ether complex, NMP = N-methyl-2-pyrrolidone, OAc = acetoxy, T ₃ P = propylphosphonic anhydride, P2O5 = phosphorus pentoxide, PE = petroleum Ether, PG = protective group, Pd-C = palladium on activated carbon, PdCl ₂ (dppf)-CH ₂ Cl ₂ = 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride ( II) Dichloromethane complex, Pd ₂ (dba) ₃ = ginseng (dibenzylideneacetone) dipalladium(0), Pd(OAc) ₂ = palladium(II) acetate, Pd(OH) ₂ = hydroxide Palladium, Pd(PPh ₃ ) ₄ = tetrakis(triphenylphosphine) palladium(0), PTSA = p-toluenesulfonic acid, R = any group, RT = room temperature, SFC = supercritical fluid chromatography, S- PHOS = 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, T3P = propylphosphonic anhydride, TBAI = tetrabutylammonium iodide, TEA = triethylamine, TFA = trifluoroacetic acid, THF = tetrahydrofuran, TMEDA = N,N,N',N'-tetramethylethylenediamine, ZnCl ₂ =zinc chloride, Xantphos = 4,5-bis(diphenylphosphino)-9,9-di Methyl 𠮿

.

Where A, L, X, n, and m are compounds of formula I as described herein, they can be synthesized similar to literature procedures and/or as depicted in, for example, Scheme 1 .

Program 1 Correspondingly, using a suitable base and solvent (such as sodium bicarbonate in DCM), make 4a,5,6,7,8,8a-hexahydro-4H-pyrido[4,3-b][1,4 Oxazin-3-one1 With intermediates2 Reaction in the presence of a urea-forming reagent (such as bis(trichloromethyl) carbonate) yields the compound of formula I (step a ). Other urea-forming reagents include, but are not limited to, phosgene, trichloromethyl chloroformate, (4-nitrophenyl) carbonate, or 1,1'-carbonyldiimidazole. This type of reaction and the use of these reagents are widely described in the literature (eg G. Sartori et al.,Green Chemistry 2000 ,2 , 140). Those skilled in the art will recognize that due to the reactivity and stability of the amine chloride formed in the middle and to avoid the formation of undesirable symmetrical urea by-products, the order of addition of reagents in this type of reaction may be important.

Compounds of formula (Ic) described herein can be prepared similar to compounds of formula (I), as described herein in Schemes 1 to 18. For example, similar to the procedure described in Scheme 1 above, using 4a,5,6,7,8,8a-hexahydro-4H-pyrido[4,3-b][1,4]oxazine -3-one 1 is reacted with intermediate 2a to produce the compound of formula (Ic) (Scheme 1A, step a).

Scheme 1A Intermediate 1 can be synthesized as shown, for example, in Scheme 2 and/or similar to methods described in the literature.

Scheme 2 Therefore, a suitable base (such as sodium carbonate or potassium carbonate, sodium hydroxide, or sodium acetate) can be used in a suitable solvent (such as THF, water, acetone, or a mixture thereof), using (for example) chloroformyl chloride or bromoethyl Acyl chloride 4 (where "LG" indicates a suitable leaving group (such as Cl or Br)) makes 3-aminohexahydropyridin-4-ol derivative 3 (where "PG" indicates a suitable protecting group (such as Cbz or Boc protection Group)) acetylation to provide intermediate 5 ( step a ).

The intermediate 5 can be cyclized to intermediate 6 using methods well known in the industry, for example, by treating 5 with sodium hydride in THF or potassium tributoxide in IPA and water ( step b ). Reactions of this type are described in the literature (eg Z. Rafinski et al., J. Org. Chem. 2015 , 80 , 7468; S. Dugar et al., Synthesis 2015 , 47 (5), 712; WO2005/066187).

Use methods known in the industry (for example, TFA used in DCM at a temperature between 0°C and room temperature (Boc group), using hydrogen in a suitable catalyst (such as Pd or Pd(OH) _{2 on} charcoal) In the presence (Cbz group) in a suitable solvent (eg MeOH, EtOH, EtOAc or mixtures thereof) and as (eg) TW Greene and PGM Wuts, "Protective Groups in Organic Chemistry", 4th edition, 2006, Wiley NY (Explained) Remove the protecting group in intermediate 6 to provide intermediate 1 ( step c ).

Intermediate 1 can be obtained as a mixture of diastereomers and mirror isomers, or as a single stereoisomer, depending on whether cis- or trans-3-aminohexahydropyridine is used in its synthesis -4-Alcohol derivative 3 in racemic mixture or in mirror-isomerically pure form. Intermediate 3 is commercially available, and its synthesis has also been described in the literature (eg WO2005/066187; WO2011/0059118; WO2016/185279).

Optically pure cis-configuration intermediates 1B and 1C can be commercially available, for example, according to Scheme 3 , by using methods known in the industry, such as by crystallization of diastereomeric salts or chiral separation by chiral chromatography ( Cis-racemic)-4a,5,6,7,8,8a-hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one ( 1A ) (visual The situation is obtained in the form of a salt, for example hydrochloride) ( step a ).

Program 3 In some embodiments, the intermediate2 systemB type,C type,D Type orE Type intermediate.B type,C type,D Type orE Type intermediates can be prepared, for example, by the synthetic procedures outlined in Schemes 4, 5, 6 and 7.

Type B intermediates (where R ¹ is as defined herein) can be prepared by a variety of conditions, which can be exemplified by the general synthetic procedures outlined in Scheme 4 .

Program 4 From aryl or heteroaryl halides7 (Where X¹ Is selected from Cl, Br or I and A is as defined herein), starting with LiHMDS orn- BuLi, preferablyn- A solution of BuLi in a solvent such as THF, diethyl ether, n-pentane, n-hexane or a mixture thereof, preferably THF, and in a temperature range between -20°C and -78°C, preferably at -78 The lithium halogen exchange reaction is carried out at ℃ to produce the corresponding lithiated aryl or heteroaryl intermediate. Nucleophilic addition of in-situ prepared lithiated aryl or heteroaryl intermediates in a solvent such as THF and preferably at a temperature of -78°C8 Type ketone (where R¹ , M and n are as defined herein) to obtain the corresponding tertiary alcohol9 (step a ).

Subsequent elimination of the third hydroxyl group using acidic conditions (e.g. 4 M HCl in dioxane in a solvent such as MeOH or preferably TFA in DCM), along with the removal of the Boc protecting group produces the corresponding olefin 10 ( step b ).

Using a catalyst (e.g. Pd(OH) ₂ or Pd/C) in a solvent such as THF, MeOH, EtOH, EtOAc or a mixture thereof, preferably Pd/C in THF to make the olefin 10 at (for example) hydrogen atmospheric pressure Heterogeneous catalytic hydrogenation yields type B intermediates ( step c ).

Intermediate 8 is commercially available and/or can be prepared similar to the methods described in the literature, such as Bioorg. Med. Chem. Lett. 2011 , 21 (18), 5191, WO2012/155199, WO2016/180536, Bioorg. Med. Chem. Lett. 2008 , 18 (18), 5087, WO2007/117557, J. Am. Chem. Soc. 2017 , 139 (33), 11353, J. Med. Chem. 2017 , 60 (13), 5507 .

Type C intermediates (where A is as defined herein and n = 1, 2, or 3) can be prepared by a variety of conditions, which can be exemplified by the general synthetic procedure outlined in Scheme 5 .

Program 5 Treatment of aryl or heteroaryl compounds with a base (eg NaOH or KOH) in a solvent such as EtOH or MeOH and in a temperature range between room temperature and 80°C, preferably at about the reflux temperature of the mixture11 (Wherein A is as defined herein, preferably where A is substituted heteroaryl as defined herein, and most preferably substituted indolyl as defined herein) and ketone12 (Where n is as defined herein) a mixture that produces olefins13 (step a ).

Subsequently, a transition metal catalyst (e.g. PtO ₂ ) is used in a polar solvent such as MeOH, EtOH, AcOEt, AcOH or a mixture thereof, preferably a mixture of EtOH/AcOH from low pressure to high pressure at about room temperature, preferably at Heterogeneous catalytic hydrogenation is carried out at a hydrogen pressure of about 5 bar to produce intermediate 14 ( step b ).

Removal of the Boc protecting group in a solvent such as MeOH using acidic conditions (eg, treatment with TFA in DCM or preferably 4 M HCl in dioxane) produces a corresponding C -type intermediate ( step c ).

In some embodiments, intermediate 14 is an intermediate of formula 14a , wherein ring A is a heteroaryl group containing a secondary amine group (ie, "-NH-", such as in indolyl) and m and n are As defined herein. For example, as outlined in Scheme 6 , intermediate 14a can be converted to a D -type intermediate, where A is a heteroaryl group containing at least one nitrogen atom, m and n are as defined herein and R ¹⁴ is selected from alkyl, Cycloalkyl, hydroxyalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl, preferably selected from methyl, cyclopropyl, cyclopropylmethyl, hydroxyethyl, oxetane -3-yl and oxetan-3-ylmethyl.

酸(步驟 a )。 Program 6 Therefore, the intermediate14a By using a suitable base (eg NaH, KH, NaHMDS, LiHMDS, LDA, preferably NaH) in a suitable solvent such as DMF, THF, dioxane or mixtures thereof, preferably DMF and between -78 Within the temperature range between ℃ and room temperature, preferably at 0 ℃, after adding compound R¹⁴ -LG (where LG represents an appropriate breakaway group, such as chlorine, bromine, iodine, OSO₂ Alkyl (e.g. mesylate (methanesulfonate), OSO₂ Fluoroalkyl (such as trifluoromethanesulfonate (trifluoromethanesulfonate) or OSO₂ Aryl (such as tosylate (p-toluenesulfonate))) toN -Functionalized to get correspondingN -Functionalized compounds15 , Where R¹⁴ As above for intermediatesD As defined. Those skilled in the art will realize that depending on R¹⁴ Nature, other or different reagents can be applied, such as in R¹⁴ In the case of cyclopropyl, use cyclopropyl in the presence of copper (II) acetate and alkali (such as DMAP and NaHMDS) in solvents such as toluene at temperatures up to the boiling point of the solvent

acid(step a ).

Deprotection of compound 15 using the same conditions as described above for compound 14 (see Scheme 5, step c) gave the D -type intermediate ( step b ).

In one embodiment, intermediate D is an E -type indazole derivative, wherein m, n, and R ¹⁴ are as defined herein. In addition to the procedures outlined in Scheme 6 , Type E intermediates can also be prepared by a variety of conditions, specifically by the general synthetic procedures outlined in Scheme 7 .

Program 7 Correspondingly, in a sealed reaction vessel at elevated temperature (e.g. 120°C) the intermediate16 (Wherein PG is a protecting group, such as Boc, Cbz or Bn, and m and n are as described herein) and R¹⁴ NHNH₂ Type hydrazine derivatives (wherein R¹⁴ (As described herein) Condensation in solvents such as n-BuOH, DMA, DMF, DMSO or mixtures thereof, preferably in n-BuOH, produces indazole compounds17 (step a ).

Subsequently, using, for example, acidic conditions, such as HCl in dioxane or TFA in DCM, preferably 4 M HCl in dioxane, in a solvent such as MeOH, preferably in a room temperature The treatment is carried out at a temperature to remove the protecting group (in the case of Boc group) to obtain an E -type intermediate ( step b ).

In some embodiments, intermediate 2 is an F -type, G -type, H -type, J -type, K -type, L -type, and M -type intermediate. F -type, G -type, H -type, J -type, K -type, L -type and M -type intermediates can be prepared by methods well known to those skilled in the art and as exemplified by the general synthetic procedures outlined in Scheme 8 Wherein A, m and n are as described herein, R ¹⁵ and R ¹⁶ are each independently selected from alkyl, cycloalkyl, hydroxyalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl, Preferably selected from methyl, cyclopropyl, cyclopropylmethyl, hydroxyethyl, oxetan-3-yl and oxetan-3-ylmethyl; and R ¹⁷ is selected from substituted Or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted alkyl.

Scheme 8 is commercially available or according to literature (e.g. J. Am. Chem. Soc. 2017 , 139 (33), 11353, J. Med. Chem. 2017 , 60 (13), 5507, RSC Advances 2015 , 5 (61 ), 40964) prepared by the method described in intermediate 18 (where A, m and n are as described herein and PG is a suitable protecting group, such as Boc, Cbz or Bn group) carbonyl group can be well known in the industry Reduction, for example, using NaBH ₄ in MeOH to obtain intermediate 19 ( step a ).

Apply methods known in the industry (e.g. TFA in DCM or 4 M HCl in dioxane at a temperature between 0°C and room temperature (Boc group), use hydrogen in a suitable catalyst (e.g. Charcoal-loaded Pd or Pd(OH) ₂ ) in the presence of (Cbz group) in a suitable solvent (such as MeOH, EtOH, EtOAc or mixtures thereof) and such as (for example) TW Greene and PGM Wuts, "Protective Groups in Organic Chemistry" , 4th edition, 2006, described in Wiley NY) removing the protecting group from intermediate 19 to provide intermediate G ( step b ).

Use a suitable base in a suitable solvent (such as sodium hydride in DMF) at a temperature between 0 °C and the boiling temperature of the solvent, using R ¹⁵ LG-type alkylating agent (where LG is suitable for leaving the group, for example Chlorine, bromine, iodine, OSO ₂ alkyl (e.g. mesylate group (methanesulfonate group), OSO ₂ fluoroalkyl (e.g. trifluoromethanesulfonate group (trifluoromethanesulfonate group) or OSO _{A 2} aryl group (eg, tosylate group (p-toluenesulfonate group)), and R ¹⁵ is as defined herein, alkylates the hydroxyl group of intermediate 19 to obtain intermediate 20 ( step c ).

Using methods well known in the industry and as described above ( step b ), removal of the protecting group from intermediate 20 yields intermediate F ( step d ).

By using an alkylation reaction, such as the widely described Wittig or Horner Emmons reaction, for example, using 2-(diethoxyphosphoryl) ethyl acetate and LiHMDS in dioxane at a temperature in the range of 0 ℃ to the boiling point of the solvent, intermediate 18 can be converted to intermediate 21, wherein R ^a train alkyl, preferably methyl or ethyl based (step e).

The double bond in intermediate 21 can be reduced by hydrogenation, for example, in the presence of a suitable catalyst (such as Pd-C) in a suitable solvent (such as MeOH, EtOH or EtOAc, or a mixture thereof) to produce intermediate 22 ( Step f ).

The reduction of the ester functional group in intermediate 22 using, for example, LiBH ₄ in THF at a temperature ranging from 0°C to the boiling point of the solvent provides intermediate 23 ( step g ).

Using methods well known in the industry and as described above ( step b ), removal of the protecting group from intermediate 23 yields intermediate G ( step h ).

Using the conditions described above ( step c ), using R ¹⁶ LG type alkylating agent (where LG is suitable for leaving the group and R ¹⁶ is as described herein), the hydroxyl group of intermediate 23 is alkylated to obtain an intermediate 24 ( Step i ).

Using methods well known in the industry and as explained above ( step b ), removal of the protecting group from intermediate 24 yields intermediate H ( step j ).

Adding an R ¹⁷ M-type organometallic compound to intermediate 18 (where M is (for example) MgCl, MgCl or Li and R ^{17 is} as described herein) provides intermediate 25 ( step k ). This type of reaction is well known in the industry and described in the literature ( J. Med. Chem. 1989 , 32 (1), 105, J. Med. Chem. 2014 , 57 (4), 1543, Bioorg. Med. Chem Lett. 2015 , 25 (13), 2720).

Using methods well known in the industry and as described above ( step b ), removal of the protecting group from intermediate 25 provides intermediate J (step 1).

Using the conditions as described above ( step c ), using R ¹⁵ LG type alkylating agent (where LG is suitable for leaving the group and R ^{15 is} as described herein) to alkylate the hydroxyl of intermediate 25 to obtain intermediate 26 ( Step m ).

Using methods well known in the industry and as explained above ( step b ), removal of the protecting group from intermediate 26 provides intermediate K ( step n ).

Apply methods known in the industry and described in the literature (e.g. J. Med. Chem. 2003 , 46 (25), 5445; WO2016/205590), for example by using, for example, methyltriphenyl bromide in toluene Wittigene alkylation of phosphonium and potassium tributoxide or LiHMDS in THF can convert intermediate 18 to intermediate 27 ( step o ).

Apply (for example) hydrogenation conditions (for example, hydrogen in the presence of a suitable catalyst (for example, Pd-C or PtO ₂ )) or use 9-borane bicyclo (3.3.1) nonane in THF (similar to literature methods, for example WO2007/002057) The double bond of intermediate 27 is reduced to obtain intermediate 28 ( step p ).

Using methods well known in the industry and as explained above ( step b ), removal of the protecting group from intermediate 28 provides intermediate L ( step q ).

The ketone of intermediate 18 is converted using aminosulfuran such as DAST using, for example, fluorination conditions to obtain intermediate 29 ( step r ).

Using methods well known in the industry and as described above ( step b ), removal of the protecting group from intermediate 29 provides intermediate M ( step s ).

In some embodiments, intermediate 2 is an N -type and O -type intermediate (where A, m, n, and R ¹⁵ are as described herein) by methods well known to those skilled in the art and as described by Scheme 9 Prepared as exemplified by the general synthetic procedure outlined in.

Program 9 Accordingly, reducing agents (such as NaBH in MeOH) can be used₄ ) Handling intermediates30a (Where A, m, and n are as defined herein, PG represents a suitable protecting group, such as Boc, Cbz, or Bn, and Y is a methyl group, which is commercially available or prepared by literature methods, for exampleBioorg. Med. Chem. Lett. 2006 ,16 (14), 3668; WO2013/179024) to produce intermediates31 . This type of reaction is also described in the literature (eg WO2013/179024) (step a ).

Alternatively, it can be prepared from intermediate 30b (where Y is a carboxyl group, which is commercially available or is similar to the method described in the literature, by using a suitable reducing agent (for example, borane tetrahydrofuran complex in a solvent such as THF) For example, Bioorg. Med. Chem. 2013 , 21 (15), 4600; WO2016/109501) prepares intermediate 31 . This type of reaction is also widely described in the literature, such as Bioorg. Med. Chem. 2013 , 21 (15), 4600) ( step a ).

Using methods well known in the industry and as explained above, removal of the protecting group from intermediate 31 provides intermediate N ( step b ).

Using the conditions as described above, using the R ¹⁵ LG-type alkylating agent (where LG is suitable for leaving the group and R ¹⁵ as described herein) to alkylate the hydroxyl group of intermediate 31 to obtain intermediate 32 ( step c ) .

Applying methods well known in the industry and removing the protecting group from intermediate 32 as described under step 8 of Scheme 8 provides intermediate O ( step d ).

In another embodiment, Intermediate 2 is a P -type intermediate, where A is as defined herein, m is 1 or 2, Ar represents aryl and HET represents heterocyclyl or heteroaryl. Intermediates of this type can be prepared similar to literature methods (eg Bioorg. Med. Chem. 2013 , 21 (7), 1756) or as exemplified by the synthetic procedures outlined in Scheme 10 .

Program 10 Intermediate33 (Where Ar is an aryl group and HET is a heteroaryl or heterocyclic group) the carbonyl group can be obtained by methods well known in the industry (for example, NaBH used in MeOH₄ ) To reduce to obtain the intermediate34 (step a ).

The hydroxyl group of intermediate 34 can be converted into a suitable leaving group (e.g. chlorine, bromine, OSO ₂ alkyl group (e.g. methanesulfonate group (methanesulfonate group), OSO by reaction with thionyl chloride in toluene _2- fluoroalkyl (such as trifluoromethanesulfonate (trifluoromethanesulfonate) or OSO ₂ aryl (such as tosylate (p-toluenesulfonate)), such as chloro), to Intermediate 34 is obtained ( step b ).

If necessary, in the presence of KI, use a suitable base and solvent (such as TEA or Huenig's base in AcCN) to make intermediate 35 and commercially available mono-protected hexahydropyrazine (m = 1) or High hexahydropyrazine (m = 2) 36 (where PG is a protecting group, such as Boc, Cbz or Bn) reacts to produce intermediate 37 ( step c ).

Using methods well known in the industry and as explained above, removal of the protecting group from intermediate 37 provides intermediate P ( step d ).

In another embodiment, intermediate 2 is a Q -type intermediate, where A is as defined herein, m is 1 or 2, Ar represents aryl and HET represents heteroaryl. Intermediates of this type may be similar to literature methods (eg Bioorg. Med. Chem. Lett. 2006 , 16 (16), 4349; Bioorg. Med. Chem. Lett. 2010 , 20 (12), 3788) and the protocol Prepared as exemplified by the synthetic procedure outlined in 11 .

Scheme 11 makes aryl or heteroaryl aldehyde 38 and mono-protected hexahydropyrazine (m = 1) or homohexahydropyrazine (m = 2) 36 (where PG is a suitable protecting group, such as Boc group and Benzotriazole) is condensed in, for example, refluxing toluene under azeotropic removal of H ₂ O to obtain intermediate 39 ( step a ).

Intermediate 39 is reacted in situ with Ar/HETCH ₂ MX-type benzyl Grignard reagent or zinc reagent 40 (where MX is a group such as MgCl, MgBr, ZnCl, or ZnBr) to obtain intermediate 41 ( step b ).

Using methods well known in the industry and as explained above, removal of the protecting group from intermediate 41 provides intermediate Q ( step c ).

In another embodiment, intermediate 2 where X = N is an R -type and S -type intermediate, where m and R ¹⁴ are as defined herein and R ¹⁸ and R ¹⁹ are each independently selected from hydrogen, substituted, or Unsubstituted alkyl, cyano, alkoxy and halogen, where substituted alkyl is as defined herein. Intermediates of this type can be prepared similar to literature methods (eg WO2007/098418) and as exemplified by the synthetic procedures outlined in Scheme 12 .

Scheme 12 Indole intermediate 42 can be reacted with mono-protected hexahydropyrazine (m = 1) or homohexahydropyrazine (m = 2) 36 (where PG is a suitable protecting group, such as Boc, Cbz or Bn group) Group, and the LG is appropriately freed of groups, such as -OAc or iodine, to produce intermediate 43 ( step a ). This type of reaction is described in the literature (eg WO2007/098418).

Applying methods well known in the industry and as explained above, removing the protecting group from intermediate 43 simultaneously or sequentially provides intermediate R ( step b ).

By means well known in the art, the indole protecting group is selectively removed from intermediate 43 to obtain intermediate 44 ( step c ). Using R ¹⁴ LG type compounds, intermediate 44 can be converted to intermediate 45 ( step d ) by methods known in the industry and as explained under scheme 6, step a. Using methods well known in the industry and as explained above, removal of the protecting group from intermediate 45 provides intermediate S ( step e ).

In another embodiment, intermediate 2 is a T -type intermediate, where A is as defined herein, m is 1 or 2 and R ¹ is selected from substituted or unsubstituted alkyl, substituted or unsubstituted Substituted cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. Intermediates of this type can be prepared similar to literature methods (eg Tetrahedron Letters 1990 , 31 (39), 5547) or as exemplified by the synthetic procedures outlined in Scheme 13 .

The carbonyl group in intermediate 46 can be reacted with amine 36 by reductive amination by methods well known in the industry, for example by acid (eg TiCl ₄ ) catalysis to produce an imine, which is then hydrogenated using a reducing agent (eg cyanoborohydride) Sodium) directly reduced in situ to the corresponding amine intermediate 47 ( step a ).

Using methods well known in the industry and as previously explained, removal of the protecting group from intermediate 47 provides intermediate T ( step b ).

Scheme 13 In another embodiment, intermediate 2 is a U -shaped intermediate, wherein A is pyrazole substituted with an aryl group and m is as defined herein. Intermediates of this type can be prepared similar to literature methods (eg J. Med. Chem. 2018 , 61 (7), 3008) or as exemplified by the synthetic procedures outlined in Scheme 14 .

Program 14 Intermediate48 The ketone in it reacts with N,N-dimethylformamide dimethyl acetal and hydrazine dihydrochloride to produce pyrazole intermediate49 (step a ).

酸反應，使用試劑乙酸銅(II)及吡啶以促進反應，從而形成中間體50 (步驟b )。應用業內熟知之方法且如上文所闡述，自中間體50 去除保護基團提供中間體U (步驟c )。Then make aryl-

For the acid reaction, the reagents copper(II) acetate and pyridine are used to promote the reaction to form intermediate 50 ( step b ). Using methods well known in the industry and as explained above, removal of the protecting group from intermediate 50 provides intermediate U ( step c ).

In some embodiments, intermediate 2 is a V -type intermediate, where m and n are as described herein, A is optionally substituted aryl or heteroaryl ring, and R ²¹ to R ²³ are each independently Selected from hydrogen, substituted or unsubstituted (cyclo)alkyl, (cyclo)alkoxy, substituted or unsubstituted aryl, R ^b R ^c N, cyano, heterocyclic, mesylate Group and halogen, wherein substituted alkyl, aryl and heteroaryl are as defined herein. Intermediates of this type can be prepared by methods well known in the industry and as exemplified by the general synthetic procedures outlined in Scheme 15 .

Program 15 Commercially available intermediates51 (Where PG represents a suitable protecting group and X is bromine or iodine) and compounds that are commercially available or prepared by methods known in the industry52 (Where FG represents a suitable functional group, such as chlorine, bromine, iodine, -OSO₂ Alkyl (e.g. mesylate (methanesulfonate), -OSO₂ Fluoroalkyl (such as trifluoromethanesulfonate (trifluoromethanesulfonate) or -OSO₂ Aromatic groups (such as tosylate groups (p-toluenesulfonate groups)) undergo cross-coupling reactions, such as Negishi, Heck, Stille, Suzuki, Tsubaki ( Sonogashira) or Buchwald-Hartwig coupling reaction (step a ). This type of reaction is widely described in the literature and is well known to those skilled in the art.

酸52a (FG = B(OH)₂ )或

酸酯52b (FG =例如4,4,5,5-四甲基-2-苯基-1,3,2-二氧雜硼雜環戊烷(頻哪醇)酯)反應，以產生中間體53 (步驟a )。此類型之鈴木反應廣泛闡述於文獻(例如A. Suzuki, Pure Appl. Chem.1991 ,63 , 419-422；A. Suzuki, N. Miyaura, Chem. Rev.1995 ,95 , 2457-2483；A. Suzuki, J. Organomet. Chem.1999 ,576 , 147-168；V. Polshettiwar等人，Chem. Sus. Chem.2010 ,3 , 502-522)中且為熟習此項技術者所熟知。或者，可應用鈀觸媒(例如四(三苯基膦)-鈀(0)、乙酸鈀(II)或二氯[1,1`-雙(二苯基膦基)二茂鐵]-鈀(II)二氯甲烷加成物)在適宜鹼(例如碳酸銫或磷酸鉀)存在下於諸如甲苯、THF、二噁烷、水或其混合物等溶劑中，在介於室溫與溶劑或溶劑混合物之沸點之間的溫度下在交叉偶合反應中使用芳基三氟硼酸鹽或雜芳基三氟硼酸鹽52c (FG = BF<sub>3</sub> )。For example, a suitable catalyst (such as dichloro[1,1`-bis(diphenyl) can be used in a suitable solvent (such as dioxane, dimethoxyethane, water, toluene, DMF, or a mixture thereof) (Phosphino)-ferrocene] palladium (II) dichloromethane adduct, tetrakis (triphenylphosphine) palladium (0) or palladium (II) acetate with triphenylphosphine) and a suitable base (e.g. Na ₂ CO ₃ , NaHCO ₃ , KF, K ₂ CO ₃ or TEA) at a temperature between room temperature and the boiling point of the solvent or solvent mixture, the intermediate 51 is commercially available or used such as (for example) Dennis G. Hall (editor), "Boronic Acids-Preparation and Applications in Organic Synthesis and Medicine", 1st Edition, 2005, John Wiley & Sons, New York).

Acid 52a (FG = B(OH) ₂ ) or

Acid ester 52b (FG = eg 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane (pinacol) ester) reacts to produce an intermediate Body 53 ( step a ). This type of Suzuki reaction is widely described in the literature (eg A. Suzuki, Pure Appl. Chem. 1991 , 63 , 419-422; A. Suzuki, N. Miyaura, Chem. Rev. 1995 , 95 , 2457-2483; A. Suzuki, J. Organomet. Chem. 1999 , 576 , 147-168; V. Polshettiwar et al., Chem. Sus. Chem. 2010 , 3 , 502-522) and well known to those skilled in the art. Alternatively, a palladium catalyst (for example, tetrakis(triphenylphosphine)-palladium(0), palladium(II) acetate or dichloro[1,1`-bis(diphenylphosphino)ferrocene]-palladium (II) dichloromethane adduct) in the presence of a suitable base (eg cesium carbonate or potassium phosphate) in a solvent such as toluene, THF, dioxane, water or mixtures thereof, at a temperature between room temperature and the solvent or solvent The aryl trifluoroborate or heteroaryl trifluoroborate 52c (FG = BF ₃ ) is used in the cross-coupling reaction at a temperature between the boiling points of the mixture.

Alternatively, a suitable catalyst and solvent (such as tetrakis(triphenylphosphine)-palladium(0) in DMF) can be used to make intermediate 51 at a temperature between room temperature and the boiling point of the solvent or solvent mixture React with aryl or heteroaryl stannane 52d (where FG is Sn(alkyl) ₃ and alkyl is preferably n-butyl or methyl) to provide intermediate 53 ( step a ). This type of Stiller reaction is well known in the industry and described in the literature, such as Org. React. 1997 , 50 , 1-652, ACS Catal. 2015, 5 , 3040-3053.

In addition, suitable catalysts and solvent systems (such as [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium(II) and copper(I) iodide in DMA or in THF can be used Or tetrakis(triphenylphosphine)palladium(0) in DMF), at a temperature between room temperature and the boiling point of the solvent, the intermediate 51 and the aromatic or heterocyclic group commercially available or prepared by literature methods An aryl zinc halide 52e (where FG is ZnHal and Hal is preferably bromine or iodine) is reacted to provide intermediate 53 ( step a ). This type of root bank reaction is well known in the industry and is also described in the literature, such as Org. Lett. , 2005 , 7, 4871, ACS Catal. 2016 , 6 (3), 1540-1552, Acc. Chem. Res. 1982, 15 (11), pp. 340-348. Alternatively, Intermediate 53 can be applied by literature methods (for example 51 with Zn powder in the presence of trimethyl-chloro-silane-and 1,2-dibromoethane under a suitable solvent such as DMA or the like as the reaction) Intermediate 51 ( Where X system (for example) iodine is converted into the corresponding zinc substance and prepared by coupling these zinc substances with aryl or heteroaryl bromide or aryl or heteroaryl iodide under the conditions mentioned before.

Alternatively, an appropriate photocatalyst (eg [Ir{dF(CF ₃ )ppy}2(dtbpy)]PF ₆ ([4,4′-bis(1,1-dimethylethyl Group)-2,2′-bipyridine-N1,N1′]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl-N]phenyl-C]iridium (III) hexafluorophosphate), nickel catalyst (such as NiCl ₂ glyme (dichloro(dimethoxyethane) nickel)), 4,4′-di-tert-butyl-2,2′-linked Pyridine and ginseng (trimethylsilyl) silane, intermediate 51 (where X is preferably bromine) and aryl bromide or heteroaryl in the presence of a suitable base (eg anhydrous sodium carbonate) in a solvent such as DME Bromide 52f (where FG represents bromine) undergoes cross-electrophilic coupling. This type of reaction is described in the literature, for example J. Am. Chem. Soc. 2016 , 138 , 8084. ( Step a ).

Applying methods well known in the industry and removing the protecting group from intermediate 53 as described, for example, under step 2 of Scheme 2 , provides intermediate V ( step b ).

Alternatively, intermediate 53 can be prepared from intermediate 51 and aryl or heteroaryl bromide 54 that are commercially available or prepared by methods known in the industry, using the transformation described under step a before applying to provide intermediate 55 ( Step c ).

The same synthesis strategy as previously explained under step a can be applied to further react intermediate 55 with compound 56 to provide intermediate 53 ( step d ).

R ^b R ^c N type (where R ^b is hydrogen, alkyl or aryl, and R ^c is alkyl or aryl or where R ^b and R ^c together with the nitrogen atom to which they are attached form optionally further substituted 4 Member to 11 member, monocyclic or bicyclic heterocyclic ring) Intermediate 53 (where R ²³ represents an amine group) can, for example, react from 55 with a primary or secondary amine R ^b R ^c NH and use (for example) suitable Catalyst (e.g. Pd(OAc) ₂ , Pd ₂ (dba) ₃ ), ligand (e.g. BINAP, Xphos, BrettPhos, RuPhos), base (e.g. Cs ₂ CO ₃ , K ₂ CO ₃ , KOT-Bu, LiHMDS, K ₃ PO ₄ ) and a solvent (for example, toluene, THF, dioxane). This type of Buchwald-Hartwig reaction is known in the industry and described in the literature (eg Angew. Chem. Int. Ed. 2008 , 47, 6338; Chem. Rev. 2008 , 108 , 3054; J. Organomet. Chem. 2018 , 861 , 17) ( step d ).

In some embodiments, the compound of formula (I) is a compoundId andIe , Where m and n are as described in this article, R^{twenty one} And R^{twenty two} Each is independently selected from hydrogen, substituted or unsubstituted (cyclo)alkyl, haloalkyl, (cyclo)alkoxy, substituted or unsubstituted aryl, R^b R^c N, cyano, heterocycle, methylsulfonyl and halogen, X is Hal, A is optionally substituted aryl or optionally substituted heteroaryl, C is optionally substituted aryl or contains At least one 4-membered to 7-membered heterocyclic ring connected to the nitrogen atom of ring A. Intermediates of this type can be obtained by methods well known in the industry andProgram 16 Prepared as exemplified by the general synthetic procedure outlined in.

Scheme 16 may be applied in the industry and as well known methods of (e.g.) the Scheme 2 as set forth in step c of Intermediate removal of protective groups 55 to give intermediate 57 (step a).

Intermediate 50 and Intermediate 1 can be coupled under the conditions set forth in Scheme 1, Step a to provide Compound Id ( Step b ).

酸或

酸酯(例如頻哪醇酯)，以產生中間體58 (步驟c )。The bromine or iodine substituent in compound 1d can be converted to the method described in the literature or as outlined in Scheme 15, step a

Acid or

An acid ester (eg pinacol ester) to produce intermediate 58 ( step c ).

For example, the reaction conditions described under step a in Scheme 15 can be used to make intermediate 58 commercially available or prepared by literature methods and wherein FG is an appropriate functional group (e.g. chlorine, bromine, OSO ₂ alkyl (e.g. mesylate (methane sulfonate), - OSO ₂ fluoroalkyl (e.g. triflate group (trifluoromethanesulfonate group), or -OSO ₂ aryl group (e.g. tosylate (P-toluenesulfonate group)) of compound 59 is reacted with Suzuki to provide compound 1e ( step d ).

Applying (for example) the conditions set forth under step 15 of Scheme 15 , compound 1e (wherein ring C is a 4- to 7-membered heterocyclic ring, which is connected to ring A via its nitrogen) can be (for example) by compound 1d and compound 60 Prepared by the Buchwald-Hartwig coupling reaction ( step e ).

In some embodiments, intermediate 2 is a W -type, X -type, and Y -type intermediate, where m and n are as described herein, L is a covalent bond and A is a 5-membered heteroaryl ring, which is further viewed The situation is substituted with a further substituted aryl ring. Compounds of this type can be prepared by methods well known in the industry or by the methods exemplified in Schemes 17, 18 and 19 below.

酸61a (B(OR^a )₂ = B(OH)₂ )或

酸酯61b (例如B(OR^a )₂ = 4,4,5,5-四甲基-2-苯基-1,3,2-二氧雜硼雜環戊烷(頻哪醇)酯))進行鈴木偶合反應，以提供中間體63 (步驟a )。 W -type intermediates where each Y is independently CH or a heteroatom (eg, a heteroatom selected from N, O, and S) can be prepared by a variety of conditions, which can be general synthetic procedures outlined in Scheme 17 Instantiation. For example, if the 5-membered heteroaryl ring system in compound 62 is substituted with bromine for 1H-pyrrole, 1H-imidazole, 1H-pyrazole, or 1H-triazole, then methods known in the industry can be applied and the steps in Scheme 15 can be applied a . As explained below, R ²⁷ and R ²⁸ are each independently selected from hydrogen, substituted or unsubstituted (cyclo)alkyl, haloalkyl, (cyclo)alkoxy, substituted or unsubstituted Aryl, R ^b R ^c N, cyano, substituted or unsubstituted heteroaryl, heterocycle, methylsulfonyl and halogen, optionally substituted phenyl-

Acid 61a (B(OR ^a ) ₂ = B(OH) ₂ ) or

Acid ester 61b (eg B(OR ^a ) ₂ = 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane (pinacol) ester) ) Perform a Suzuki coupling reaction to provide intermediate 63 ( step a ).

Intermediate 63 can be reacted with compound 64 , which is commercially available or prepared similarly to literature methods, for example, using photo-redox conditions as explained under step a of Scheme 15 , to obtain intermediate 65 ( step b ).

Applying methods well known in the industry and as described, for example, under step 2 of Scheme 2 , removing the protecting group from intermediate 65 provides intermediate W ( step c ).

Program 17 X Type intermediates (wherein the 5-membered heteroaryl ring system 1,2,4-oxadiazole, which is further substituted at the 3-position by a phenyl ring that is further substituted as appropriate) can be, for example, as outlined in Scheme 18 Synthesis procedure.

Scheme 18 can, for example, use hydroxylamine hydrochloride and K ₂ CO ₃ in EtOH at a temperature ranging from room temperature to the boiling point of the solvent to make benzonitrile 66 and 66 commercially available or synthesized by methods known in the industry. Hydroxylamine reacts to provide amide oxime 67 ( step a ).

Intermediate 67 is coupled with activated carboxylic acid 68a (X = H) or carboxychloride 68b (X = Cl) where PG represents a suitable protecting group, followed by cyclization to provide intermediate 69 ( step b ). This type of amide coupling is widely described in the literature, and can be used by using materials such as CDI, DCC, HATU, HBTU, HOBT, TBTU, T3P, or Mukaiyama reagent (Mukaiyama T. Angew. Chem., Int. Ed. Engl. 1979 , 18 , 707) and other coupling agents in a suitable solvent (for example, DMF, DMA, DCM, or dioxane), depending on the situation in the base (such as NEt ₃ , DIPEA (Schneider base) or DMAP) Exist to complete. Alternatively, the carboxylic acid 68a can be converted to its acetyl chloride 68b by treatment with, for example, pure or optionally sulfenyl chloride or oxalyl chloride in a solvent (such as DCM). In a suitable solvent (e.g. DCM or DMF) and a base (e.g. NEt ₃ , Schneider base, pyridine, DMAP or bis(trimethylsilyl)amine lithium) at a temperature range from 0°C to the reflux temperature of the solvent or solvent mixture At the internal temperature, reacting the acetyl chloride with the intermediate 68 produces the acylated form of the intermediate 67 , which can be dehydrated at, for example, elevated temperature to provide the intermediate 69 ( step b ).

Applying methods well known in the industry and removing the protecting group from intermediate 69 as described under (for example) step 2 of Scheme 2 provides intermediate X ( step c ).

Y -type intermediates (wherein the 5-membered heteroaryl ring system 1,3,4-oxadiazole, which is further substituted at the 5-position with a phenyl ring that is further substituted as appropriate) can be described by the literature or For example, it is prepared by the general synthetic procedure outlined in Scheme 19.

Conditions under Scheme 19 18 step b applications set forth, the use of activated carboxylic acid 68a (X = H) or a carboxylic acyl chloride 68b (X = Cl) prepared by the method well known in the industry to make it commercially available or acyl The base hydrazide 70 is acetylated to provide the intermediate 71 ( step a ).

Subsequently, the intermediate 71 is cyclized and dehydrated, for example, by heating to produce an intermediate 72 ( step b ).

Using methods well known in the industry and as described, for example, under Scheme 2, Step c , removal of the protecting group from Intermediate 72 provides Intermediate Y (Step c).

與雜環胺2 在鹼及脲形成試劑存在下反應，其中A、L、X、m及n係如本文所定義

以形成該等式(I)化合物。In one aspect, the present invention provides a process for making a compound of formula (I) as described herein, which comprises: 4a, 5, 6, 7, 8, 8a-hexahydro-4H-pyrido[4,3 -b][1,4]oxazin-3-one ( 1 )

Reacts with heterocyclic amine 2 in the presence of base and urea-forming reagents, where A, L, X, m and n are as defined herein

To form the compound of formula (I).

與雜環胺2a 在鹼及脲形成試劑存在下反應，其中A、L、X、m、n及R²⁰ 至R²³ 係如本文所定義

以形成該等式(Ic)化合物。In another aspect, the present invention provides a process for making a compound of formula (Ic) as set forth herein, which comprises: using 4a, 5, 6, 7, 8, 8a-hexahydro-4H-pyrido[4, 3-b][1,4]oxazin-3-one ( 1 )

Reaction with heterocyclic amine 2a in the presence of a base and a urea-forming reagent, where A, L, X, m, n and R ²⁰ to R ²³ are as defined herein

To form the compound of formula (Ic).

In one embodiment, a process of the present invention is provided, wherein the base is sodium bicarbonate.

In one embodiment, the process of the present invention is provided, wherein the urea-forming agent is selected from bis(trichloromethyl) carbonate, phosgene, trichloromethyl chloroformate, (4-nitrophenyl) carbonate And 1,1'-carbonyldiimidazole, preferably wherein the urea forming reagent is bis(trichloromethyl) carbonate. In one aspect, the invention provides compounds of formula (I) as set forth herein, which are manufactured according to any of the processes set forth herein.

MAGL inhibitory activity The compounds of the present invention are MAGL inhibitors. Therefore, in one aspect, the present invention provides the use of compounds of formula (I) and (Ic) as set forth herein for inhibiting MAGL in mammals.

In another aspect, the present invention provides compounds of formula (I) and (Ic) as set forth herein, for use in a method of inhibiting MAGL in a mammal.

In another aspect, the present invention provides the use of compounds of formula (I) and (Ic) as set forth herein for the preparation of a medicament for inhibiting MAGL in mammals.

In another aspect, the invention provides a method for inhibiting MAGL in a mammal, the method comprising administering to the mammal an effective amount of a compound of formula (I) and (Ic) as set forth herein.

The MAGL inhibitory activity of the compound was analyzed by measuring the enzymatic activity of MAGL, which was carried out by tracking the hydrolysis of 4-nitrophenyl acetate to produce 4-nitrophenol absorbed at 405-412 nm (GG Muccioli, G. Labar, DM Lambert, Chem. Bio. Chem. 2008 , 9 , 2704-2710). This analysis is abbreviated as "4-NPA analysis" hereinafter.

The analysis was performed with a total volume of 40 µL in a 384-well analysis plate (black, with a transparent bottom, and the surface is unbound, Corning Ref. 3655). Compound dilutions were prepared in polypropylene plates in 100% DMSO (VWR Chemicals 23500.297) in a 3-fold dilution step so that the final concentration range in the analysis was 25 µM to 1.7 nM. Add 1 µL of compound dilution (100% DMSO) to 19 µL of MAGL (recombinant wild type) in analysis buffer (50 mM TRIS (GIBCO, 15567-027), 1 mM EDTA (Fluka, 03690-100 ml)) ). The plate was shaken at 2000 rpm (Variomag Teleshake) for 1 min, and then incubated at room temperature for 15 min. To start the reaction, add 20 µL of 4-nitrophenyl acetate (Sigma N-8130) in analysis buffer containing 6% EtOH. The final concentration in the analysis was 1 nM MAGL and 300 µM 4-nitrophenyl acetate. After shaking (1 min, 2000 rpm) and incubating at room temperature for 5 min, the absorbance at 405 nm was first measured (Molecular Devices, SpectraMax Paradigm). Then, after incubating at room temperature for 80 min, the second measurement was performed. From the two measurement values, the slope is calculated by subtracting the first measurement value from the second measurement value.

Alternatively, the MAGL inhibitory activity of the compound is analyzed by measuring the enzyme activity by tracking the hydrolysis of the natural substrate 2-arachidene glycerol (2-AG) to produce arachidic acid, which can be traced by mass spectrometry . This analysis is abbreviated as "2-AG analysis" hereinafter.

The 2-AG analysis was performed in a 384-well analysis plate (PP, Greiner catalog number 784201) with a total volume of 20 µL. Compound dilutions were prepared in polypropylene plates in 100% DMSO (VWR Chemicals 23500.297) in a 3-fold dilution step so that the final concentration range in the analysis was 12.5 µM to 0.8 pM. Add 0.25 µL of compound dilution (100% DMSO) to 9 µL in analysis buffer (50 mM TRIS (GIBCO, 15567-027), 1 mM EDTA (Fluka, 03690-100ml), 0.01% (v/v) Tween ) In MAGL. After shaking, the plate was incubated at room temperature for 15 min. To start the reaction, add 10 µL of 2-arachidonyl glycerol in analysis buffer. The final concentration in the analysis was 50 pM MAGL and 8 µM 2-arachidene glycerol. After shaking and incubating at room temperature for 30 min, the reaction was quenched by adding 40 µL of acetonitrile containing 4 µM d8-arachioleic acid. The amount of arachidic acid was tracked by an online SPE system (Agilent Rapidfire) coupled with a triple quadrupole mass spectrometer (Agilent 6460). A C18 SPE column (G9205A) was used in the ACN/water phase setting. After mass conversion of arachidic acid 303.1 à 259.1 and d8-arachidic acid 311.1 à 267.0, the mass spectrometer was operated in negative electrospray mode. The activity of the compound is calculated based on the ratio of intensity [arachidonic acid/d8-arachidonic acid]. Table 1

[a]: If not otherwise indicated (see [b]), measure the activity in the 4-NPA analysis; [b]: measure in the 2-AG analysis.

In one aspect, the present invention provides compounds of formula (I) and (Ic) and pharmaceutically acceptable salts or esters thereof as set forth herein, wherein the compounds of formula (I) and (Ic) and their pharmaceutically acceptable salt or ester thereof for the inhibition of the IC ₅₀ MAGL below 25 μM, preferably less than 10 μM, more preferably less than 5 μM, as measured in the MAGL analysis set forth herein.

In one embodiment, (Ic) a compound of formula (I) set forth herein and in the IC and the pharmaceutically acceptable salts thereof or the ester ₅₀ (MAGL inhibition) values range between 0.000001 μM and 25 μM, a particular compound The IC ₅₀ value is between 0.000005 µM and 10 µM, and the IC ₅₀ value of other specific compounds is between 0.00005 µM and 5 µM, as measured in the MAGL analysis described in this article.

In one embodiment, the present invention provides compounds of formula (I) and (Ic) and their pharmaceutically acceptable salts or esters as set forth herein, wherein these compounds of formula (I) and (Ic) and their pharmaceutically Acceptable salts or esters have an IC ₅₀ for MAGL of less than 25 µM, preferably less than 10 µM, more preferably less than 5 µM, as measured in the analysis including the following steps: a) Provide formula (I ) Or (Ic) a solution of a compound or a pharmaceutically acceptable salt or ester in DMSO; b) provide MAGL (recombinant wild type) in assay buffer (50 mM ginseng (hydroxymethyl) aminomethane; 1 mM Solution in ethylenediaminetetraacetic acid); c) add 1 µL of the compound solution from step a) to 19 µL of the MAGL solution from step b); d) shake the mixture at 2000 rpm for 1 min; e) in the chamber Incubate at temperature for 15 min; f) Add 20 µL of 4-nitrophenyl acetate to analysis buffer (50 mM ginseng (hydroxymethyl) aminomethane; 1 mM ethylenediaminetetraacetic acid; 6% EtOH) G) shake the mixture at 2000 rpm for 1 min; h) incubate at room temperature for 5 min; i) measure the absorbance of the mixture at 405 nm for the first time; j) incubate at room temperature for another 80 min ; K) the second measurement of the absorbance of the mixture at 405 nm; l) the absorbance measured under k) minus the absorbance measured under i) and calculating the slope of the absorbance; where: i) in the analysis After step f), the concentration of the compound of formula (I) or (Ic) or a pharmaceutically acceptable salt or ester thereof is in the range of 25 µM to 1.7 nM; ii) After step f) in the analysis, MAGL The concentration is 1 nM; iii) After step f) in the analysis, the concentration of 4-nitrophenyl acetate is 300 µM; and iv) Repeat steps a) to l) at least 3 times for each use Compounds of formula (I) or (Ic) or their pharmaceutically acceptable salts or esters in different concentrations.

Use of compounds of the invention In one aspect, the invention provides compounds of formula (I) and (Ic) as set forth herein, which are useful as therapeutically active substances.

In another aspect, the present invention provides the use of compounds of formula (I) and (Ic) as set forth herein for the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer and/or in mammals Mental disorders.

In one embodiment, the present invention provides the use of compounds of formula (I) and (Ic) as set forth herein for the treatment or prevention of neuroinflammation and/or neurodegenerative diseases in mammals.

In one embodiment, the present invention provides the use of compounds of formula (I) and (Ic) as set forth herein for the treatment or prevention of neurodegenerative diseases in mammals.

In one embodiment, the present invention provides the use of compounds of formula (I) and (Ic) as set forth herein for the treatment or prevention of cancer in mammals.

In one aspect, the present invention provides the use of compounds of formula (I) and (Ic) as described herein for the treatment or prevention of multiple sclerosis, Alzheimer's disease, Parkinson's disease in mammals , Muscular atrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, hepatocellular carcinoma, colon cancer, ovarian cancer, neuropathic pain, chemotherapy induced Neuropathy, acute pain, chronic pain, and/or spasm associated with pain.

In a preferred embodiment, the present invention provides the use of compounds of formula (I) and (Ic) as described herein for the treatment or prevention of multiple sclerosis, Alzheimer's disease and/or Par Kinson's disease.

In a particularly preferred embodiment, the present invention provides the use of compounds of formula (I) and (Ic) as described herein for the treatment or prevention of multiple sclerosis in mammals.

In one aspect, the present invention provides compounds of formula (I) and (Ic) as described herein for use in the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, and/or mental disorders in mammals.

In one embodiment, the present invention provides compounds of formula (I) and (Ic) as described herein for use in the treatment or prevention of neuroinflammatory and/or neurodegenerative diseases in mammals.

In one embodiment, the present invention provides compounds of formula (I) and (Ic) as described herein for use in the treatment or prevention of cancer in mammals.

In one embodiment, the present invention provides compounds of formula (I) and (Ic) as described herein for use in the treatment or prevention of neurodegenerative diseases in mammals.

In one aspect, the invention provides compounds of formula (I) and (Ic) as described herein for use in the treatment or prevention of multiple sclerosis, Alzheimer's disease, Parkinson's disease, muscle in mammals Atrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety disorder, migraine, depression, hepatocellular carcinoma, colon cancer, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy , Acute pain, chronic pain and/or spasm associated with pain.

In a preferred embodiment, the present invention provides compounds of formula (I) and (Ic) as described herein for use in the treatment or prevention of multiple sclerosis, Alzheimer's disease and/or Parkinson's in mammals disease.

In particularly preferred embodiments, the present invention provides compounds of formula (I) and (Ic) as described herein for use in the treatment or prevention of multiple sclerosis in mammals.

In one aspect, the present invention provides the use of compounds of formula (I) and (Ic) as set forth herein for the preparation or treatment of mammalian neuroinflammation, neurodegenerative diseases, pain, cancer and And/or potions of mental disorders.

In one embodiment, the present invention provides the use of compounds of formula (I) and (Ic) as set forth herein for the preparation of a medicament for the treatment or prevention of neuroinflammation and/or neurodegenerative diseases in mammals.

In one embodiment, the present invention provides the use of compounds of formula (I) and (Ic) as set forth herein for the preparation of a medicament for the treatment or prevention of neurodegenerative diseases in mammals.

In one embodiment, the present invention provides the use of compounds of formula (I) and (Ic) as set forth herein for the preparation of a medicament for the treatment or prevention of cancer in mammals.

In another aspect, the present invention provides the use of compounds of formulae (I) and (Ic) as set forth herein for the preparation of medicaments for the treatment or prevention of the following conditions in mammals: multiple sclerosis, az Hemer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety disorder, migraine, depression, hepatocellular carcinoma, colon cancer occurrence, ovarian cancer , Neuropathic pain, neuropathy induced by chemotherapy, acute pain, chronic pain and/or spasm associated with pain.

In a preferred embodiment, the present invention provides the use of compounds of formulae (I) and (Ic) as set forth herein for the preparation or treatment of multiple sclerosis, Alzheimer's disease and mammals in mammals /Or a medicine for Parkinson's disease.

In a particularly preferred embodiment, the present invention provides the use of compounds of formula (I) and (Ic) as set forth herein for the preparation of a medicament for the treatment or prevention of multiple sclerosis in mammals.

In one aspect, the invention provides a method for treating or preventing neuroinflammation, neurodegenerative diseases, pain, cancer, and/or mental disorders in a mammal, the method comprising administering to the mammal an effective amount as described herein The compound of formula (I) or (Ic) as stated.

In one embodiment, the present invention provides a method for treating or preventing neuroinflammation and/or neurodegenerative diseases in a mammal, the method comprising administering to the mammal an effective amount of formula (I) as described herein Or (Ic) compound.

In one embodiment, the present invention provides a method for treating or preventing a neurodegenerative disease in a mammal, the method comprising administering to the mammal an effective amount of a compound of formula (I) or (Ic) as described herein .

In one aspect, the invention provides for the treatment or prevention of multiple sclerosis in mammals, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, A method of stroke, epilepsy, anxiety, migraine, depression, and/or pain, which method comprises administering to the mammal an effective amount of a compound of formula (I) or (Ic) as set forth herein.

In a preferred embodiment, the present invention provides a method for treating or preventing multiple sclerosis, Alzheimer's disease and/or Parkinson's disease in a mammal, the method comprising administering to the mammal an effective amount Compounds of formula (I) or (Ic) as set forth herein.

In a particularly preferred embodiment, the present invention provides a method for treating or preventing multiple sclerosis in a mammal, the method comprising administering to the mammal an effective amount of a compound of formula (I) or (Ic) as described herein .

Pharmaceutical Composition and Administration In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described herein and a therapeutically inert carrier.

The compounds of formula (I) and their pharmaceutically acceptable salts and esters can be used as medicaments (for example, in the form of pharmaceutical preparations). Such pharmaceutical preparations can be taken orally (for example, in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (for example, by nasal spray Form) or transrectally (eg, in the form of suppositories). However, the administration can also be achieved parenterally (eg, intramuscularly or intravenously (eg, in the form of an injection solution)).

The compound of formula (I) and its pharmaceutically acceptable salts and esters can be treated with pharmaceutical inert inorganic or organic adjuvants to produce tablets, coated tablets, dragees and hard gelatin capsules. Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. can be used as adjuvants for tablets, dragees and hard gelatin capsules, for example.

Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols.

Suitable adjuvants for producing solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like.

Suitable adjuvants for injection solutions are, for example, water, alcohol, polyol, glycerin, vegetable oil, and the like.

Suitable adjuvants for suppositories are, for example, natural or hardened oils, paraffin waxes, fats, semi-solid or liquid polyols, and the like.

In addition, these pharmaceutical preparations may contain preservatives, solubilizers, viscosity enhancing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for changing the osmotic pressure, buffers, masking Agents or antioxidants. It may also contain other substances of therapeutic value.

The dosage can vary within wide limits and of course it should be suitable for the individual needs of each specific situation. Generally speaking, in the case of oral administration of a daily dose of about 0.1 mg/kg body weight to 20 mg/kg body weight, preferably about 0.5 mg/kg body weight to 4 mg/kg body weight (e.g. about 300 mg/person) It is preferably divided into 1 to 3 individual doses (which may consist of (for example) the same amount) as appropriate. However, it should be clear that the upper limit given in this article may be exceeded when indicated.

According to the present invention, the compound of formula (I) or pharmaceutically acceptable salts and esters thereof can be used to treat or prevent microvascular complications related to type 2 diabetes (such as (but not limited to) diabetic retinopathy, diabetic neuropathy, and diabetic nephropathy ), coronary artery disease, obesity and potentially inflammatory diseases, chronic inflammatory and autoimmune/inflammatory diseases.

Examples The present invention will be more fully understood by referring to the following examples. However, the scope of patent application should not be interpreted as limiting the scope of examples.

In the case where the preparation example is obtained as a mixture of mirror isomers, it can be by the method described herein or by methods known to those skilled in the art (eg chiral chromatography (eg chiral SFC) or crystallization) To separate pure mirror isomers.

If not specified otherwise, all reaction examples and intermediates were prepared under an argon atmosphere.

Method A1 Example 1 rac - (4aR, 8aS) -6- ( 4- benzhydryl-piperidine-1-carbonyl) -4,4a, 5,7,8,8a- hexahydro-pyrido [4 ,3-b][1,4] oxazin- 3 -one to 4-benzylhexahydropyridine-1-carboxylic acid 4-nitrophenyl ester (40 mg, 96 µmol, BB1) in DMF (1 mL), TEA (19.4 mg, 26.8 µL, 192 µmol), racemic-cis-hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3(4H )-Ketone (15 mg, 96 µmol, ChemBridge Corporation), and the resulting reaction mixture was heated at 80° C. for 18 hours to complete the reaction. The reaction mixture was diluted with H ₂ O and NaHCO ₃ and extracted three times with EtOAc. The combined organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated. The product was purified by preparative HPLC (Gemini NX column) using a gradient (20: 80 to 98: 2) of ACN: H ₂ O (containing 0.1% FA) to yield the desired compound as a colorless solid (0.015 g; 36.5 %). MS (ESI): m/z = 434.2 [M+H] ⁺ .

Method A2 Example 2 Racemic- (4aR,8aS)-6-(4-(5- chloro- 1-( cyclopropylmethyl )-1H- indol- 3 -yl ) hexahydropyridine- 1- carbonyl ) Hexahydro -2H- pyrido [4,3-b][1,4] oxazine -3(4H) -one to bis(trichloromethyl) carbonate (45.3 mg, 153 µmol, CAS RN 32315- 10-9) and NaHCO ₃ (73.3 mg, 873 µmol) in ice-cold suspension in DCM (1 mL) were added 5-chloro-1-(cyclopropylmethyl)-3-(hexahydropyridine-4 at one time) -Yl)-1H-indole acetate formate (76.1 mg, 218 µmol, BB2), and the mixture was stirred at room temperature overnight. After cooling in an ice bath, racemic-cis-hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3(4H)-one dihydrochloride (50 mg , 218 µmol, ChemBridge Corporation) and DIPEA (112 mg, 152 µL, 870 µmol). The suspension was stirred at room temperature for 6 hours. The reaction mixture was poured onto H ₂ O and DCM, and the layers were separated. The aqueous layer was extracted twice with DCM. The organic layer was dried over MgSO ₄ , filtered, treated with silica gel and evaporated. By silica gel chromatography, using a MPLC system on a 4 g column using DCM: MeOH gradient (100: 0 to 90: 10) for dialysis to purify the compound to obtain the desired compound as a colorless gum (0.070 g; 68.1%). MS (ESI): m/z = 471.2 [M+H] ⁺ .

Method A3 Example 22 (+)- or (-)- cis- 6-(4-(5- chloro- 1-( oxetan- 3 -yl )-1H- indol- 3 -yl ) hexahydro Pyridine- 1- carbonyl ) hexahydro -2H- pyrido [4,3-b][1,4] oxazin -3(4H) -one to bis(trichloromethyl) carbonate (26.6 mg, 89.6 µmol ) An ice-cold solution in DCM (1 mL) was added NaHCO ₃ (32.3 mg, 384 µmol) and racemic-cis-hexahydro-2H-pyrido[4,3-b][1,4]oxazine -3(4H)-one (20 mg, 128 µmol, ChemBridge Corporation), and the mixture was stirred at room temperature overnight. After cooling the suspension to 0°C, 5-chloro-1-(oxetan-3-yl)-3-(hexahydropyridin-4-yl)-1H-indole (37.2 mg, 128 µmol, BB10) and DIPEA (49.7 mg, 67.1 µL, 384 µmol). The mixture was stirred at room temperature for 1 hour. The reaction mixture was poured onto water and DCM, and the layers were separated. The aqueous layer was extracted twice with DCM. The organic layer was dried over MgSO ₄ , filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography using a MPLC system on a 4 g column using a gradient of DCM:MeOH (100:0 to 90:10) to obtain the desired compound as a colorless solid (0.025 g; 41.3% ). MS (ESI): m/z = 473.2 [M+H] ⁺ .

Method A4 Example 67 (4aR,8aS)-6-(4-((3 -cyclopropyl -1,2,4 -oxadiazol- 5- yl )(4- fluorophenyl ) methyl ) hexahydropyridine -1- carbonyl ) hexahydro -2H- pyrido [4,3-b][1,4] oxazin -3(4H) -keto (4aR,8aS)-3-oxohexahydro-2H- Pyrido[4,3-b][1,4]oxazine-6(5H)-carboxylic acid 4-nitrophenyl ester (50 mg, 156 µmol, BB15a) and DIPEA (50.3 mg, 68 µL, 389 µmol ) Add 3-cyclopropyl-5-((4-fluorophenyl)(hexahydropyridin-4-yl)methyl)-1,2,4-oxadiazole to the suspension in ACN (0.7 mL) A solution of hydrochloride (55.2 mg, 163 µmol, BB39) in ACN (0.7 mL), and the solution was stirred at room temperature overnight. The light yellow solution was stirred at reflux for 23 h and then evaporated. The residue was dissolved in 2 M Na ₂ CO ₃ aqueous solution and EtOAc, and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layer was washed once with water, dried over MgSO ₄ , filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography using a MPLC system on a 4 g column using n-heptane: EtOAc/EtOH 3/1 gradient (70: 30 to 90: 10) to obtain a light brown solid Desired compound (0.022 g; 29.2%). MS (ESI): m/z = 484.2 [M+H] ⁺ .

酸(15.9 mg, 101 µmol, CAS RN 1679-18-1)、(4aR,8aS)-6-(3-(4-溴苯基)氮雜環丁烷-1-羰基)六氫-2H-吡啶并[4,3-b][1,4]噁嗪-3(4H)-酮(40 mg, 101 µmol，實例110)、碳酸鉀(70.1 mg, 507 µmol)、水(100 µL)及四(三苯基膦)鈀(0) (5.86 mg, 5.07 µmol, CAS RN 14221-01-3)於THF (1 mL)中之懸浮液在80℃下攪拌3 h。將反應混合物傾倒於水及EtOAc上，且分離各層。將水層用EtOAc萃取兩次。使有機層經MgSO₄ 乾燥，過濾，經矽膠處理並蒸發。藉由矽膠層析，在4 g管柱上使用MPLC系統利用正庚烷: EtOAc/EtOH (3/1 v/v)之梯度(70 : 30至10 : 90)進行溶析來純化化合物，產生呈無色固體之期望化合物(0.020 g; 46.3%)。MS (ESI): m/z = 426.16 [M+H]⁺ 。 Method A5 Example 111 (4aR,8aS)-6-(3-(4'- chloro- [1,1'- biphenyl ]-4 -yl ) azetidine- 1- carbonyl ) hexahydro -2H- Pyrido [4,3-b][1,4] oxazin -3(4H) -one (4-chlorophenyl)

Acid (15.9 mg, 101 µmol, CAS RN 1679-18-1), (4aR,8aS)-6-(3-(4-bromophenyl)azetidine-1-carbonyl)hexahydro-2H- Pyrido[4,3-b][1,4]oxazin-3(4H)-one (40 mg, 101 µmol, example 110), potassium carbonate (70.1 mg, 507 µmol), water (100 µL) and A suspension of tetrakis(triphenylphosphine)palladium(0) (5.86 mg, 5.07 µmol, CAS RN 14221-01-3) in THF (1 mL) was stirred at 80°C for 3 h. The reaction mixture was poured onto water and EtOAc, and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layer was dried over MgSO ₄ , filtered, treated with silica gel and evaporated. Compounds were purified by silica gel chromatography using a MPLC system on a 4 g column using n-heptane: EtOAc/EtOH (3/1 v/v) gradient (70: 30 to 10: 90) for elution. The desired compound as a colorless solid (0.020 g; 46.3%). MS (ESI): m/z = 426.16 [M+H] ⁺ .

Method A6 Example 128 (4aR,8aS)-6-(3-(4-(3 -methoxyazetidin- 1 -yl ) phenyl ) azetidine- 1- carbonyl ) hexahydro- 2H - pyrido [4,3-b] [1,4] oxazin -3 (4H) - one to a solution of the (4aR, 8aS) -6- (3- (4- bromophenyl) azetidin Alkane-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (50 mg, 127 µmol, Example 110) in tert-butanol ( 1 mL) solution was added XPhos (5.44 mg, 11.4 µmol, CAS RN 564483-18-7), ginseng (dibenzylideneacetone) dipalladium (0) chloroform adduct (3.94 mg, 3.8 µmol, CAS RN 52522-40-4), 3-methoxyazetidine hydrochloride (23.5 mg, 190 µmol, CAS RN 148644-09-1) and cesium carbonate (165 mg, 507 µmol), and the mixture was heated To 85 ℃ for 21 h. The mixture was filtered and the filtrate was evaporated. The product was purified on a preparative HPLC (Gemini NX column) using a gradient of ACN: water (containing 0.1% formic acid) (20: 80 to 98: 2) to obtain the desired compound (0.006 g; 11.8%) as a colorless solid. MS (ESI): m/z = 401.2 [M+H] ⁺ . Alternatively, the reaction can be carried out in a microwave oven at 100°C.

Method A7 Example 225 (4aR,8aS)-6-[3-[4-( oxetan- 3 -yl ) phenyl ] azetidine- 1- carbonyl ]-4,4a,5,7, 8,8a -Hexahydropyrido [4,3-b][1,4] oxazin- 3 -one Add (Ir[dF(CF ₃ )ppy] ₂ (dtbpy) to a 5 mL vial equipped with a stir bar ) PF ₆ (1.42 mg, 1.27 µmol, CAS RN 870987-63-6), 3-bromooxetane (17.4 mg, 127 µmol, CAS RN 39267-79-3), (4aR, 8aS)-6 -(3-(4-bromophenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one ( 50 mg, 127 µmol, Example 110), ginseng (trimethylsilyl) silane (31.5 mg, 39.1 µL, 127 µmol, CAS RN 1873-77-4) and anhydrous sodium carbonate (26.9 mg, 254 µmol). The vial was sealed and placed under argon, after which DME (1 mL) was added. Add nickel(II) chloride ethylene glycol dimethyl ether complex (2.79 mg, 12.7 µmol, CAS RN 29046-78-4) and 4,4'-di-tert-butyl-2,2 to separate vials '-Bipyridine (3.4 mg, 12.7 µmol, CAS RN 72914-19-3). The front catalyst vial was sealed, purged with argon and then DME (0.4 mL) was added. The front catalyst vial was sonicated for 5 min, after which 0.4 mL (0.5 mol% catalyst, 0.01 eq) was injected into the reaction vessel. The reaction mixture was degassed with argon. The reaction was stirred and irradiated with a 420 nm lamp for 4 h. The reaction was quenched by exposure to air, filtered and washed with a small volume of EtOAc. The filtrate was treated with silica gel and evaporated. Purified by silica gel chromatography on a 4 g column using MPLC (ISCO) system using n-heptane: EtOAc/EtOH 3/1 (v/v) gradient (70: 30 to 10: 90) The compound provided the desired compound as a light yellow solid (0.010 g; 21.2%). MS (ESI): m/z = 372.3 [M+H] ⁺ .

酸(100.0 mg, 0.280 mmol, BB38)及2-溴-5-氯苯甲腈(120.5 mg, 0.560 mmol, CAS RN 57381-37-0)及CsF (127 mg, 0.840 mmol)於DMF (5 mL)中之溶液添加Pd(dppf)Cl₂ (40.8 mg, 0.060 mmol)，將混合物在90℃下在N₂ 氣氛下攪拌12 h。過濾該混合物且將濾液用水(20 mL)稀釋並用EtOAc萃取(10 mL三次)，將合併之有機相用鹽水洗滌，經Na₂ SO₄ 乾燥並濃縮，藉由製備型HPLC (FA)純化殘餘物且凍乾，獲得呈白色固體之期望化合物(38.8 mg, 30.7%)。MS (ESI): m/z = 451.1 [M+H]⁺ 。 Method A8 Example 159 2-[4-[1-[(4aR,8aS)-3 -oxo- 4,4a,5,7,8,8a -hexahydropyrido [4,3-b][1 ,4] oxazine -6- carbonyl ] azetidin- 3 -yl ] phenyl ]-5- chloro - benzonitrile toward [4-[1-[(4aR,8aS)-3-pendantoxy- 4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carbonyl]azetidin-3-yl]phenyl]

Acid (100.0 mg, 0.280 mmol, BB38) and 2-bromo-5-chlorobenzonitrile (120.5 mg, 0.560 mmol, CAS RN 57381-37-0) and CsF (127 mg, 0.840 mmol) in DMF (5 mL ) Was added Pd(dppf)Cl ₂ (40.8 mg, 0.060 mmol), and the mixture was stirred at 90° C. for 12 h under N ₂ atmosphere. The mixture was filtered and the filtrate was diluted with water (20 mL) and extracted with EtOAc (10 mL three times), the combined organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated, the residue was purified by preparative HPLC (FA) And lyophilized to obtain the desired compound (38.8 mg, 30.7%) as a white solid. MS (ESI): m/z = 451.1 [M+H] ⁺ .

Method A9 Examples 75 and 76 (4aR,8aS)-6-(3-(R or S)-(1-(2- chloro- 4-( trifluoromethyl ) phenoxy ) ethyl ) azetidine Alkane- 1- carbonyl ) hexahydro -2H- pyrido [4,3-b][1,4] oxazin -3(4H) -one and (4aR,8aS)-6-(3-(S or R )-(1-(2-chloro-4-(trifluoromethyl)phenoxy)ethyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][ 1,4]oxazine-3(4H)-one to 3-(1-(2-chloro-4-(trifluoromethyl)phenoxy)ethyl)azetidine 2,2,2- A solution of trifluoroacetate (BB94) (133.5 mg, 207 µmol) in a mixture of CH ₃ CN (517 µL) and 2-propanol (517 µL) was added with DIPEA (66.8 mg, 90.3 µL, 517 µmol) and ( 4aR,8aS)-3-oxohexahydro-2H-pyrido[4,3-b][1,4]oxazine-6(5H)-carboxylic acid 4-nitrophenyl ester (66.5 mg, 207 µmol, BB15a). The reaction vial was stirred at 90°C for 21 h. Add another portion of (4aR,8aS)-3-oxohexahydro-2H-pyrido[4,3-b][1,4]oxazine-6(5H)-carboxylic acid 4-nitrophenyl ester (19.9 mg, 62.1 µmol, BB15a) and DIPEA (8.02 mg, 10.8 µL, 62.1 µmol), and the mixture was heated to 95°C for 23 h. The crude material was subjected to reverse-phase achiral HPLC purification to yield (4aR, 8aS)-6-(3-(1-(2-chloro-4-(trifluoromethyl)phenoxy)ethyl) as a white solid ) Azetidine-1-carbonyl) hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (88 mg, 92.1%). The epimers were separated by chiral HPLC to give Example 75 (33.6 mg) and Example 76 (43.2 mg) as yellow solids. MS (ESI) of the two compounds: m/z = 462.2 [M+H] ⁺ .

Method A10 Examples 91, 96 and 97 (4aR, 8aS)-6-(3-(1-(2- fluoro- 4-( trifluoromethyl ) phenoxy ) ethyl ) azetidine- 1- Carbonyl ) hexahydro -2H- pyrido [4,3-b][1,4] oxazin -3(4H) -one and (4aR,8aS)-6-(3-((R or S)-1 -(2- fluoro-4-( trifluoromethyl) phenoxy) ethyl) azetidine-1- carbonyl) hexahydro-2H- pyrido[4,3-b][1,4] Oxazine-3(4H) -one and (4aR,8aS)-6-(3-((S or R)-1-(2- fluoro-4-( trifluoromethyl) phenoxy) ethyl) Azetidine-1- carbonyl) hexahydro-2H- pyrido[4,3-b][1,4] oxazine-3(4H) -keto 3-(1-(2-fluoro-4 -(Trifluoromethyl)phenoxy)ethyl)azetidine 2,2,2-trifluoroacetate BB97 (51.4 mg, 136 µmol) in CH ₃ CN (681 µL) added DIPEA (52.8 mg, 71.4 µL, 409 µmol) and (4aR,8aS)-3-oxohexahydro-2H-pyrido[4,3-b][1,4]oxazine-6(5H)-carboxylic acid 4-Nitrophenyl ester (43.8 mg, 136 µmol, BB15a). The reaction vial was stirred at 95 °C for 3 h. Reverse phase HPLC purification of the crude material yielded (4aR,8aS)-6-(3-(1-(2-fluoro-4-(trifluoromethyl)phenoxy)ethyl)aza as an off-white solid Cyclobutane-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (Example 91; 31 mg, 51%). MS (ESI): m/z = 446.3 [M+H] ⁺ . Chiral SFC separation of the racemic product yields (4aR,8aS)-6-(3-((R or S)-1-(2-fluoro-4-(trifluoromethyl)benzene) as a white solid Oxy)ethyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (15.9 mg, Example 96 ) And (4aR,8aS)-6-(3-((S or R)-1-(2-fluoro-4-(trifluoromethyl)phenoxy)ethyl)azetidine-1- Carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (15.2 mg, Example 97). MS (ESI) of the two compounds: m/z = 446.2 [M+H] ⁺ .

Method A11 Example 55 (4aR,8aS)-6-(3-( fluorobis (4- fluorophenyl ) methyl ) azetidine- 1- carbonyl ) hexahydro -2H- pyrido [4,3- b] [1,4] oxazine -3(4H) -one was added to an ice-cold solution of triethylamine trihydrofluoride (31.8 mg, 32.1 µL, 197 µmol) in DCM (493 µL) under argon ( (Diethylamino)difluoroammonium tetrafluoroborate (33.9 mg, 148 µmol, CAS RN 63517-29-3), and then added to (4aR,8aS)-6-(3- (Bis(4-fluorophenyl)(hydroxy)methyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3(4H )-Ketone (Example 54) (45.1 mg, 98.6 µmol), and the mixture was stirred at 0° C. for 70 min and then at room temperature for 25 min. The reaction was quenched with saturated aqueous NaHCO ₃ solution at 0°C and stored in the refrigerator overnight. The phases were separated, and the aqueous layer was extracted twice with DCM. The combined organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated to give a light colored oil. The crude material was subjected to reverse-phase HPLC purification to give the desired compound (20 mg, 41.5%) as a white solid. MS (ESI): m/z = 504.18 [M+HCOO] ^- .

Method A12 Example 224 (4aR,8aS)-6-(3-(3- chloro- 4-(3 -methylazetidin- 1 -yl ) phenyl ) azetidine- 1- carbonyl ) hexa Hydrogen -2H- pyrido [4,3-b][1,4] oxazin -3(4H) -one (4aR,8aS)-6-(3-(4-bromo-3-chlorophenyl) Azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (example 132, 0.020 g, 0.047 mmol) in di To the solution in oxane (0.5 mL) was added Pd ₂ (dba) ₃ (0.004 g, 0.0047 mmol), Xantphos (0.003 g, 0.0047 mmol) and cesium carbonate (0.030 g, 0.093 mmol). The mixture was degassed with argon, then 3-methylazetidine hydrochloride (CAS RN 1375472-05-1, 0.010 g, 0.093 mmol) was added, and the reaction mixture was heated to 100 °C for 16 h. Thereafter, 3-methylazetidine hydrochloride (0.005 g, 0.047 mmol), Pd ₂ (dba) ₃ (0.004 g, 0.0047 mmol), Xantphos (0.003 g, 0.0047 mmol) and cesium carbonate (0.015 g, 0.047 mmol), and the reaction mixture was heated to 100 °C for another 2 h. The mixture was diluted with EtOAc and washed with H ₂ O and brine. The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (0.007 g, 36%) as a yellow solid. MS (ESI): m/z = 419.3 [M+H] ⁺ .

Method B1 Example 5 (+)- cis- 6-[4-(6- fluoro -1H- indol- 3 -yl ) hexahydropyridine- 1- carbonyl ]-4,4a,5,7,8,8a - hexahydro-pyrido [4,3-b] [1,4] oxazin-3-one with EtOH on preparative chiral HPLC (Reprosil chiral NR column) (containing 0.05% of NH ₄ OAc): positive An isocratic mixture of heptane (60: 40) separated the racemate (the product of Example 7). The fractions were evaporated to obtain the desired compound (0.009 mg) as a light yellow solid. MS (ESI): m/z = 401.2 [M+H] ⁺ .

Method B2 Example 11 (+)- cis- 6-(4-( bis (4- fluorophenyl ) methyl ) hexahydropyrazine- 1- carbonyl ) hexahydro -2H- pyrido [4,3-b ][1,4] oxazin -3(4H) -one on preparative chiral HPLC (Chiralcel OD column) using EtOH (containing 0.05% NH ₄ OAc): n-heptane isocratic mixture (80: 20) Separation of the mirror image isomer of Example 12. The fractions were evaporated to obtain the desired compound (0.014 g) as a colorless solid. MS (ESI): m/z = 471.3 [M+H] ⁺ .

Method B3 Examples 31 and 32 (+)- cis- 6-(4-((R or S)-1-(4- fluorophenyl )-3 -hydroxypropyl ) hexahydropyridine- 1- carbonyl ) hexa Hydrogen -2H- pyrido [4,3-b][1,4] oxazin -3(4H) -one and (-)- cis- 6-(4-((S or R)-1-( 4- fluorophenyl )-3 -hydroxypropyl ) hexahydropyridine- 1- carbonyl ) hexahydro -2H- pyrido [4,3-b][1,4] oxazine -3(4H) -one The enantiomer of racemic Example 26 was separated from preparative chiral HPLC (Chiralpak AD column) using EtOH (containing 0.05% NH ₄ OAc): n-heptane isocratic mixture (40:60). Allow the fraction to evaporate. The residue was dissolved in EtOH, DCM and n-heptane, and evaporated again to remove excess AcOH. The compound was purified by silica gel chromatography using a MPLC (ISCO) system on a 4 g column using a gradient of DCM:MeOH (100:0 to 80:20) to provide the desired product as a colorless gum ( 0.004 g, 7.7% and 0.010 g, 19%). MS (ESI) of each stereoisomer: m/z = 420.2 [M+H] ⁺ .

Method B4 Example 94 (4aR,8aS)-6-(4-((R or S)-(3 -cyclopropyl -1,2,4 -oxadiazol- 5- yl )(4- fluorophenyl ) Methyl ) hexahydropyridine- 1- carbonyl ) hexahydro -2H- pyrido [4,3-b][1,4] oxazin -3(4H) -one by preparative chiral SFC (IA, 12 nm, 5 µm, 250 × 4.6 mm column), using an isocratic mixture of MeOH: carbon dioxide (25:75) to isolate the racemate of Example 68. The fraction containing the desired product was evaporated to obtain the desired product (0.016 g, 40.0%) as a light brown solid. MS (ESI): m/z = 484.2 [M+H] ⁺ .

method B5 Examples 114 and 115 (4aR,8aS)-6-[3-[(1R)-1-[4-( Trifluoromethyl ) Phenyl ] Ethoxy ] Azetidine -1- Carbonyl ]-4,4a,5,7,8,8a- Hexahydropyrido [4,3-b][1,4] Oxazine -3- Ketone and (4aR,8aS)-6-[3-[(1S)-[4-( Trifluoromethyl ) Phenyl ] Ethoxy ] Azetidine -1- Carbonyl ]-4,4a,5,7,8,8a- Hexahydropyrido [4,3-b][1,4] Oxazine -3- ketone By preparative chiral SFC (OZ-H, 220 nm, 250 × 10 mm column), the isomeric isomer of Example 90 was isolated using an isocratic mixture of MeOH: carbon dioxide (20:80). The fractions were evaporated to give the title product (0.005 g) as a colorless amorphous solid. MS (ESI) of two mirror isomers: m/z = 428.4 [M+H]⁺ .

Example 25 (+)- or (-)- cis- 6-(4-(5- chloro- 1-(2- hydroxyethyl )-1H- indol- 3 -yl ) hexahydropyridine- 1- carbonyl ) Hexahydro -2H- pyrido [4,3-b][1,4] oxazine -3(4H) -keto (+)- or (-)-cis-6-(4-(1- (2-((Thirdbutyldimethylsilyl)oxy)ethyl)-5-chloro-1H-indol-3-yl)hexahydropyridine-1-carbonyl)hexahydro-2H-pyrido [4,3-b][1,4]oxazin-3(4H)-one (39 mg, 67.8 µmol, Example 24) in DCM (0.5 mL) was added TFA (77.3 mg, 52.2 µL, 678 µmol), and the solution was stirred at room temperature for 1.5 hours. To the light yellow solution, THF (0.1 mL) and H ₂ O (0.1 mL) were added, and stirring was continued at room temperature for 96 hours. The reaction mixture was evaporated. The residue was poured onto saturated aqueous NaHCO ₃ and DCM, and the layers were separated. The aqueous layer was extracted twice with DCM. The organic layer was dried over MgSO ₄ , filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography using a MPLC system on a 4 g column using a gradient of DCM:MeOH (100:0 to 90:10) to provide the desired compound as a colorless solid (0.014 g; 44.8% ). MS (ESI): m/z = 461.2 [M+H] ⁺ .

Example 173 (4aR, 8aS) -6- ( 3- (4'- chloro-2 '- (meth sulfo acyl) - [1,1'-biphenyl] -4-yl) azetidine - 1- carbonyl ) hexahydro -2H- pyrido [4,3-b][1,4] oxazin -3(4H) -one treated with sodium methyl mercaptan (4.26 mg, 60.8 µmol) (4aR,8aS) -6-(3-(4'-chloro-2'-fluoro-[1,1'-biphenyl]-4-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4 ,3-b][1,4]oxazin-3(4H)-one (27 mg, 60.8 µmol, Example 133) in DMSO (0.5 mL) and stirred at 100°C overnight. Another batch of sodium methyl mercaptan (4.26 mg, 60.8 µmol) was added, and stirring was continued at 100°C for 2 h. After cooling, the mixture was poured onto water, and the layers were separated. The organic layer was extracted twice with EtOAc. The organic layer was dried over MgSO ₄ , filtered and evaporated. The obtained crude intermediate (112 mg, light yellow oil) was dissolved in DCM (0.7 mL), and m-chloroperoxybenzoic acid (98.2 mg, 195 µmol) was added at room temperature. The mixture was stirred at room temperature and continued to be stirred at room temperature for 1 h. The reaction mixture was poured onto saturated aqueous NaHCO ₃ and DCM, and the layers were separated. The aqueous layer was extracted twice with DCM. The organic layer was dried over MgSO ₄ , filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography using a MPLC system on a 4 g column using a gradient of DCM:MeOH (100:0 to 90:10) to obtain the desired intermediate sulfonylate as a colorless gum ( 0.014 g). It was dissolved in DCM (0.7 mL), and m-chloroperoxybenzoic acid (43.6 mg, 195 µmol) was added. Continue stirring at room temperature for 3 h. The reaction mixture was poured onto saturated aqueous NaHCO ₃ and DCM, and the layers were separated. The aqueous layer was extracted twice with DCM. The organic layer was dried over MgSO ₄ , filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography using a MPLC system on a 4 g column using a gradient of DCM:MeOH (100:0 to 90:10) to obtain the desired compound as a colorless solid (0.004 g; 13.0% ). MS (ESI): m/z = 504.1 [M+H] ⁺ .

酸(36 mg, 189 µmol, CAS RN 68716-47-2)及Cs₂ CO₃ (70.2 mg, 216 µmol)，且將混合物在100℃下攪拌過夜。將反應混合物傾倒於水及EtOAc上，且分離各層。將水層用EtOAc萃取兩次。使合併之有機層經MgSO₄ 乾燥，過濾並蒸發。藉由製備型HPLC (Gemini NX管柱)，使用ACN :水(含有0.1% TEA)之梯度(20: 80至98 : 2)純化產物，提供呈淺棕色固體之期望化合物(0.0038 g; 4.6%)。MS (ESI): m/z = 461.1 [M+H]⁺ 。Example 193 (4aR,8aS)-6-(3-(5-(2,4- dichlorophenyl ) pyridin -2- yl ) azetidine- 1- carbonyl ) hexahydro -2H- pyrido [ 4,3-b][1,4] oxazin -3(4H) -one under argon to (4aR,8aS)-6-(3-(5-chloropyridin-2-yl)azetidine -1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (63 mg, 180 µmol, example 181) in dioxane (0.5 mL ), add tricyclohexylphosphine (4.03 mg, 14.4 µmol, CAS RN 2622-14-2), ginseng (dibenzylideneacetone), dipalladium (0) chloroform adduct (7.44 mg, 7.18 µmol), (2,4-dichlorophenyl)

Acid (36 mg, 189 µmol, CAS RN 68716-47-2) and Cs ₂ CO ₃ (70.2 mg, 216 µmol), and the mixture was stirred at 100°C overnight. The reaction mixture was poured onto water and EtOAc, and the layers were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layer was dried over MgSO ₄ , filtered and evaporated. The product was purified by preparative HPLC (Gemini NX column) using ACN: water (containing 0.1% TEA) gradient (20: 80 to 98: 2) to provide the desired compound as a light brown solid (0.0038 g; 4.6% ). MS (ESI): m/z = 461.1 [M+H] ⁺ .

Example 218 (4aR,8aS)-6-[4-[ phenyl ( oxazin- 3 -yl ) methyl ] hexahydropyridine- 1- carbonyl ]-4,4a,5,7,8,8a -hexahydro Pyrido [4,3-b][1,4] oxazin- 3 -one 3-[phenyl(4-hexahydropyridyl)methyl]pyrazine (70 mg, 0.28 mmol, BB86) and ( 4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carboxylic acid (4-nitro A solution of phenyl)ester (intermediate BB15a) (106 mg, 0.330 mmol) in pyridine (3 mL) was stirred at 80°C for 16 h. The solution was filtered and concentrated under vacuum to obtain a residue, which was purified by preparative HPLC (basic conditions) to give (4aR, 8aS)-6-[4-[phenyl(triazine -3-yl)methyl]hexahydropyridin-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3- Ketone (5.9 mg, 5%). MS (ESI): m/z = 436.2 [M+H] ⁺ .

Example 247 (4aR,8aS)-6-[3-[4-(3- fluoropropyl ) phenyl ] azetidine- 1- carbonyl ]-4,4a,5,7,8,8a- hexa Hydropyrido [4,3-b][1,4] oxazin- 3 -one to 3-[4-(3-fluoropropyl)phenyl]azetidine (40 mg, 0.21 mmol, BB87) and a solution of DIPEA (0.07 mL, 0.41 mmol) in MeCN (0.9 mL) was added (4aR, 8aS)-3-oxo-4,4a,5,7,8,8a-hexa Hydropyrido[4,3-b][1,4]oxazine-6-carboxylic acid (4-nitrophenyl) ester (66 mg, 0.210 mmol; BB15a). The resulting mixture was stirred at 80 °C for 16 h. The solution was concentrated under vacuum to obtain a residue, which was purified by preparative HPLC (TFA conditions) to give (4aR, 8aS)-6-[3-[4-(3-fluoropropyl) as a white solid )Phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one( 16 mg, 17%, 84% purity). This material was combined with the product obtained from a second reaction of similar scale (0.23 mmol 3-[4-(3-fluoropropyl)phenyl]azetidine), and by preparative HPLC (TFA conditions) A second purification was performed to obtain the title compound as a white solid. MS (ESI): m/z = 376.3 [M+H] ⁺ .

Example 252 (4aR,8aS)-6-[4-[[3-(2 - aminoethoxy ) phenyl ] -phenyl - methyl ] hexahydropyridine- 1- carbonyl ]-4,4a,5 ,7,8,8a -hexahydropyrido [4,3-b][1,4] oxazin- 3 -one toward (2-(3-((1-((4aR,8aS)-3-side Oxyoctahydro-2H-pyrido[4,3-b][1,4]oxazine-6-carbonyl)hexahydropyridin-4-yl)(phenyl)methyl)phenoxy)ethyl) A solution of tert-butyl carbamate (Example 237; 178 mg, 300 µmol) in DCM (2.5 mL) was added TFA (274 mg, 185 µL, 2.4 mmol), and the reaction mixture was stirred at ambient temperature 3 hour. EtOAc and KHCO ₃ aqueous solution were added. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic layer was dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to give the title compound (148 mg, quantitative) as a pale yellow foam. MS (ESI): m/z = 493.3 [M+H] ⁺ .

Example 255 N-[2-[3-[2-[3-[[1-[(4aR,8aS)-3 -oxo- 4,4a,5,7,8,8a -hexahydropyrido [ 4,3-b][1,4] oxazine -6- carbonyl ]-4 -hexahydropyridyl ] -phenyl - methyl ] phenoxy ] ethylamino ]-3- pendantoxy - propyl Oxy ] ethyl ] aminocarbamic acid tert-butyl ester Add DIPEA (52.5 mg, 70.9 µL, 406 µmol) to (4aR,8aS)-6-(4-((3-(2-aminoethoxy Yl)phenyl)(phenyl)methyl)hexahydropyridine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (example 252; 50 mg, 101 µmol), 3-(2-t-boc-aminoethoxy) propionic acid (CAS RN 1260092-44-1; 23.7 mg, 101 μmol) and HATU (42.5 mg, 112 µmol) In DMF (203 µL). The mixture was stirred at ambient temperature for 18 h. Add ethyl acetate and aqueous KHCO ₃ solution. The layers were separated, and the organic phase was washed twice with water. The organic layer was dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to give the title compound (71 mg, quantitative) as a colorless oil, MS (ESI): m/z = 708.4 [M+H] ⁺ .

Example 256 N-[2-[2-[3-[2-[3-[[1-[(4aR,8aS)-3 -oxo- 4,4a,5,7,8,8a -hexahydrogen Pyrido [4,3-b][1,4] oxazine -6- carbonyl ]-4 -hexahydropyridyl ] -phenyl - methyl ] phenoxy ] ethylamino ]-3 -oxo group - propoxy] ethoxy] ethyl] carbamic acid tert-butyl ester DIPEA (52.5 mg, 70.9 μL, 406 μmol) was added to (4aR, 8aS) -6- (4 - ((3- (2-Aminoethoxy)phenyl)(phenyl)methyl)hexahydropyridine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine-3 (4H)-one (Example 252; 50 mg, 101 µmol), 13,13-dimethyl-11- pendant-4-7,12-trioxa-10-azatetradecanoic acid (CAS RN 1365655-91-9; 28.1 mg, 101 μmol) and HATU (42.5 mg, 112 µmol) in DMF (135 µL). The mixture was stirred at ambient temperature for 18 h. Add ethyl acetate and aqueous KHCO ₃ solution. The layers were separated, and the organic phase was washed twice with water. The organic layer was dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to give the title compound (76 mg, quantitative) as a colorless oil, MS (ESI): m/z = 774.4 [M+Na] ⁺ .

Example 258 (4aR,8aS)-6-[3-(4- propoxyphenyl ) azetidine- 1- carbonyl ]-4,4a,5,7,8,8a -hexahydropyrido [ 4,3-b][1,4] oxazin- 3 -one to (4aR,8aS)-6-(3-(4-hydroxyphenyl)azetidine-1-carbonyl)hexahydro-2H -Pyrido[4,3-b][1,4]oxazin-3(4H)-one (0.032 g, 96.6 µmol, BB145) and potassium carbonate (16 mg, 116 µmol) in DMF (0.4 mL) To the suspension, 1-iodopropane (19.7 mg, 11.3 µL, 116 µmol) was added, and the mixture was stirred at 50°C overnight in a sealed tube. The mixture was filtered and the filter cake was washed with a few drops of DMF. The product was purified on a preparative HPLC (YMC Triart C18 column) using a gradient of ACN: water (containing 0.1% TEA) (20: 80 to 100:0) to provide the desired compound as a colorless solid (0.013 g; 36.0%) . MS (ESI): m/z = 374.3 [M+H] ⁺ .

Example 260 2-[4-[1-[(4aR,8aS)-3 -oxo- 4,4a,5,7,8,8a -hexahydropyrido [4,3-b][1,4 ] oxazine-6-carbonyl] azetidin-3-yl] phenyl] -N- ethyl-5-methyl - amine to benzoyl (4aR, 8aS) -6- [3- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)phenyl)azetidine-1-carbonyl]-4,4a, 5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (100.0 mg, 0.230 mmol, BB91), Na ₂ CO ₃ (48.03 mg, 0.450 mmol ) And 2-bromo-N-ethyl-5-methyl-benzamide (54.86 mg, 0.230 mmol, BB92) in 1,4-dioxane (4 mL) and water (1 mL) Pd(dppf)Cl ₂ (16.58 mg, 0.020 mmol) was added, and the mixture was stirred at 100° C. under N ₂ atmosphere. After stirring at this temperature for 12 h, the mixture was poured into water (20 mL) and extracted three times with EtOAc (10 mL). The combined organic layer was washed with brine and dried over Na ₂ SO ₄ , concentrated, and the residue was purified by reverse phase flash chromatography (0.1% v/v FA), then preparative HPLC (0.225% v/v FA), The desired product was obtained as a white solid (13.8 mg, 12.5%). MS (ESI): m/z = 477.3 [M+H] ⁺ .

If not indicated otherwise, the following examples in Table 2 were synthesized from one or more suitable building blocks similar to the reaction methods described herein. Table 2

Synthesis of building blocks BB1 4- Diphenylmethyl hexahydropyridine- 1- carboxylic acid 4- nitrophenyl ester to 4-Diphenylmethyl hexahydropyridine (50 mg, 199 µmol, CAS RN 19841-73-7) TEA (40.3 mg, 55.4 µL, 398 µmol) was added to the solution in DCM (1.2 mL). While cooling to 0°C, 4-nitrophenyl chloroformate (44.1 mg, 219 µmol, CAS RN 7693-46-1) was added, and the reaction mixture was warmed to room temperature and stirred for 18 hours. The reaction mixture was diluted with DCM and then washed with _aqueous H ₂ O and saturated NaHCO use, the combined organic layers were washed with brine, dried over Na ₂ SO _4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel 10 g, eluted with 0%-50% EtOAc/n-heptane) to give the title compound (75 mg, 90.5%) as a light yellow solid. MS (ESI): m/z = 417.4 [M+H] ⁺ .

BB2 5- chloro- 1-( cyclopropylmethyl )-3-( hexahydropyridin- 4 -yl )-1H -indole (FA salt ) 4-(5-chloro-1-(cyclopropylmethyl Yl) indol-3-yl] hexahydropyridine-1-carboxylic acid tert-butyl ester (400.0 mg, 1.03 mmol) in HCl/EtOAc (4 M, 15.0 mL) was stirred at 20 °C for 15 hours. The mixture was concentrated in vacuo, and the residue was suspended in H 2 O (5 mL). The pH was adjusted to pH=7 with ammonia, and then purified by preparative HPLC (0.1% FA and ACN in H ₂ O) to obtain the title compound (215.9 mg, 62.6%) as a white solid. MS (ESI): m/z = 289.1 [M+H] ⁺ .

Intermediate: 4-(5- chloro-1-( cyclopropylmethyl)-1H- indol-3 -yl) hexahydropyridine-1- carboxylic acid tert-butyl ester (bromomethyl)cyclopropane ( 0.17 mL, 1.79 mmol; CAS RN 7051-34-5), tert-butyl 4-(5-chloro-1H-indol-3-yl)hexahydropyridine-1-carboxylate (500.0 mg, 1.49 mmol, BB9, intermediate step b), 15-crown-5 (0.06 mL, 0.300 mmol; CAS RN 33100-27-5) and sodium tert-butoxide (287.01 mg, 2.99 mmol; CAS RN 865-48-5) at The mixture in anhydrous EtOH (5 mL) was stirred at 25°C for 12 hours. The mixture was diluted with H ₂ O (20 mL), extracted three times with EtOAc (40 mL each time) and concentrated under vacuum. The residue was purified by flash silica gel column chromatography (100-200 mesh) using a gradient of PE: EtOAc (50: 1 to 20: 1) to give the title compound (400 mg, 68.8%) as a light yellow solid. MS (ESI): m/z = 411.1 [M+Na] ⁺ .

BB3 5- chloro- 1 -methyl- 3-( hexahydropyridin- 4 -yl )-1H -indole 4-(5-chloro-1-methyl-indol-3-yl)hexahydropyridine- A mixture of tert-butyl 1-carboxylate (480.0 mg, 1.38 mmol) in HCl/EtOAc (20.0 mL, 6 M) was stirred at 20°C for 15 hours. The mixture was concentrated under vacuum, adjusted to pH about 7 using aqueous ammonia, and then concentrated to obtain a residue, which was purified by preparative HPLC to obtain the title compound (172.3 mg, 49.3%) as a colorless powder. MS (ESI): m/z = 249.2 [M+H] ⁺ .

Intermediate: 4-(5- chloro-1 -methyl- indol-3 -yl) hexahydropyridine-1- carboxylic acid tert-butyl ester at 0°C to 60% NaH (119.46 mg) in mineral oil , 2.99 mmol) in THF (20 mL) was added tert-butyl 4-(5-chloro-1H-indol-3-yl)hexahydropyridine-1-carboxylate (500.0 mg, 1.49 mmol, BB9 , Intermediate step b) in THF (5 mL). The mixture was stirred at 0 °C for 0.5 hour, and then MeI (211.95 mg, 1.49 mmol) was added. The mixture was stirred at 0 °C for 1 hour, poured into H ₂ O (5 mL) and extracted with EtOAc (20 mL × 3). The combined organic layer was washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound (480 mg, 92.1%) as a pale yellow solid. MS (ESI): m/z = 349.1 [M-Boc+H] ⁺ .

BB4 4-(9H- 茀 -9- yl ) hexahydropyridine Add platinum(IV) oxide to a solution of 4-(9H-茀-9-yl)pyridine (70 mg, 288 µmol) in AcOH (1 mL) (10 mg, 44 µmol). The reaction mixture was stirred overnight at 40°C under a hydrogen atmosphere of 20 bar. The reaction mixture was filtered, and the filtrate was washed with AcOH. The solution thus obtained was concentrated in vacuo. The residue was dissolved in DCM, and the DCM was washed three times with saturated aqueous NaHCO ₃ solution. The organic layer was dried over MgSO ₄ , filtered and concentrated to obtain the desired product. (0.060 g; 83%). MS (ESI): m/z = 250.2 [M+H] ⁺ .

Intermediate : a) 4-(9H- 茀 -9- yl ) pyridine To a solution of diphenyl(4-pyridyl)methanol (135 mg, 517 µmol) in FA (2 mL) was added sulfuric acid (0.8 mL). The mixture was heated to 100 °C for 15 minutes, cooled to room temperature and poured into 20 mL of 5 N NaOH aqueous solution, which caused the product to precipitate. The product was collected by filtration to give the product as a pale yellow solid (75 mg, 60%). MS (ESI): m/z = 244.2 [M+H] ⁺ . b) Diphenyl (4- pyridyl ) methanol is added to phenyl(pyridin-4-yl)methanone (0.52 g, 2.84 mmol, CAS RN 14548-46-0) in THF (10 mL) at room temperature. The solution was added dropwise with 1 M phenylmagnesium bromide solution (9 mL, 9 mmol, CAS RN 100-58-3) in THF for 2 hours. The reaction mixture was poured onto saturated aqueous NH ₄ Cl and EtOAc, and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layer was washed with brine, dried over MgSO ₄ , filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography using a MPLC system on a 4 g column using a gradient of DCM:MeOH (100:0 to 90:10) to produce the desired compound as a colorless solid (0.290 g; 39.0% ). MS (ESI): m/z = 262.2 [M+H] ⁺ .

BB5 4- [1- (4-fluorophenyl) -3-methoxy-propyl] - piperidine-4- (1- (4-fluorophenyl) -3-methoxy-propyl) - six A solution of tert-butyl hydropyridine-1-carboxylate (95 mg, 270 µmol) in dioxane (0.3 mL) was added 4 M HCl (338 µL, 1.35 mmol) in dioxane, and the mixture Stir at room temperature for 2 h. The light yellow solution was completely evaporated. The residue was dissolved in saturated aqueous NaHCO ₃ and DCM, and the layers were separated. The aqueous layer was extracted twice with DCM. The organic layer was dried over MgSO ₄ , filtered and evaporated to give the desired compound (0.057 g; 83.9%) as a pale yellow oil. MS (ESI): m/z = 252.3 [M+H] ⁺ .

Intermediate: a) 4- [1- (4- fluorophenyl) -3-methoxy-propyl] - piperidine-1-carboxylic acid tert-butyl ester To a solution of 4- (1- (4-Fluorophenyl Base)-3-hydroxy-propyl)hexahydropyridine-1-carboxylic acid tert-butyl ester (95 mg, 282 µmol) in THF (1 mL) was added to an ice-cold solution of 55% NaH (13.5 mg, 310 µmol), and the mixture was stirred at this temperature for 30 minutes, after which iodomethane (47.9 mg, 21.1 µL, 337 µmol) was added. After stirring at this temperature for 30 minutes, the cloudy solution was allowed to warm to room temperature. After stirring at room temperature for 4 hours, the reaction mixture was poured onto H ₂ O and EtOAc, and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layer was dried over MgSO ₄ , filtered and evaporated to obtain the desired compound (0.097 g; 98.0%) as a pale yellow oil. MS (ESI): m/z = 252 [M-Boc+H] ⁺ . b) 4-[1-(4- Fluorophenyl )-3 -hydroxy - propyl ] hexahydropyridine- 1- carboxylic acid tert-butyl ester at 0 °C to 4-[3-ethoxy-1- (4-fluorophenyl)-3-oxo-propyl]hexahydropyridine-1-carboxylic acid tert-butyl ester (148 mg, 390 µmol) in THF (1.5 mL) was added borohydride at once Lithium (21.2 mg, 975 µmol), and the mixture was stirred in an ice bath for 1.25 hours. The ice bath was removed and stirring was continued at room temperature for 20 hours. The reaction mixture was poured onto saturated aqueous NH ₄ Cl and EtOAc, and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layer was dried over MgSO ₄ , filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography using a MPLC system on a 4 g column using a gradient of n-heptane: EtOAc (100:0 to 0:100) to produce the desired compound (0.097) as a colorless oil g; 73.7%). MS (ESI): m/z = 282.3 [MC ₄ H ₈ +H] ⁺ . c) 3-[4- ethoxy- 1-(4- fluorophenyl )-3 -oxo - propyl ] hexahydropyridine- 1- carboxylic acid tert-butyl ester (E) and (Z) Tert-Butyl-4-(3-ethoxy-1-(4-fluorophenyl)-3-oxoprop-1-en-1-yl)hexahydropyridine-1-carboxylate (1.74 g , 4.63 mmol) in EtOAc (17.1 mL) was added Pd/C 10% (175 mg), and the suspension was stirred at room temperature under a hydrogen atmosphere of 1.5 bar for 4 hours. The reaction mixture was filtered through a microfilter. By silica gel chromatography, using a MPLC system on a 24 g column using n-heptane: EtOAc gradient (100: 0 to 50: 50) for dialysis to purify the compound to obtain the desired compound as a colorless liquid (1.23 g; 69.8%). MS (ESI): m/z = 280 [M-Boc+H] ⁺ . d) 4-[(E) and (Z)-3- ethoxy- 1-(4- fluorophenyl )-3 -oxo - prop- 1 -enyl ] hexahydropyridine- 1- carboxylic acid Tributyl ester 2-(diethoxyphosphoryl) ethyl acetate (2.1 g, 1.86 mL, 9.36 mmol, cas RN 867-13-0) in 1,4-dioxane (9.73 mL) The solution in was added 1.0 M LiHMDS (15 mL, 15 mmol) in hexane dropwise, and the solution was stirred for 15 minutes. Combine 4-(4-fluorobenzyl)hexahydropyridine-1-carboxylic acid tert-butyl ester (2.878 g, 9.36 mmol, CAS RN 160296-40-2) in 1,4-dioxane (9.73 mL ) Is added dropwise to the mixture, and stirring under reflux is continued for more than two days. The reaction mixture was poured onto saturated aqueous NH ₄ Cl and EtOAc, and the layers were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed once with H2O, dried over MgSO _4, filtered, evaporated, and treated by silicone. By silica gel chromatography, using a MPLC system on a 40 g column using n-heptane: EtOAc gradient (100: 0 to 50: 50) for dialysis to purify the compound, resulting in the desired compound as a colorless liquid (1.74 g; 49.4%). MS (ESI): m/z = 278.2 [M-Boc+H] ⁺ .

BB6 4 - [(4-fluorophenyl) - methoxy - methyl] piperidine 4 - [(4-fluorophenyl) - methoxy - methyl] -piperidine-1-carboxylic acid tertiary A solution of butyl ester (57 mg, 176 µmol) in dioxane (200 µL) was added with 4 M HCl (220 µL, 880 µmol) in dioxane, and the mixture was stirred at room temperature for 2 hours. The light yellow solution was completely evaporated. The residue was dissolved in saturated aqueous NaHCO ₃ and DCM, and the layers were separated. The aqueous layer was extracted twice with DCM. The combined organic layers were dried over MgSO ₄ , filtered and evaporated to give the desired compound (0.036 g; 91.5%) as a light yellow oil. MS (ESI): m/z = 224.2 [M+H] ⁺ .

Intermediate: a) 4 - [(4- fluorophenyl) - methoxy - methyl] -piperidine-1-carboxylic acid tert-butyl ester 4 - ((4-fluorophenyl) (hydroxy) methyl Base) Hexahydropyridine-1-carboxylic acid tert-butyl ester (60 mg, 194 µmol, CAS RN160296-41-3) in THF (1 mL) was added to an ice-cold solution of 55% NaH (9.31 mg in mineral oil) , 213 µmol), and the mixture was stirred at this temperature for 30 minutes, after which iodomethane (33.1 mg, 14.6 µL, 233 µmol) was added. After stirring at this temperature for 30 minutes, the cloudy solution was allowed to warm to room temperature. After stirring at room temperature for 2 hours, another batch of methyl iodide (33 mg, 14.6 µL, 233 µmol) was added. After 4.5 hours, the reaction mixture was poured onto H2O and EtOAc, and the layers were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO ₄ , filtered and evaporated to obtain the desired compound (0.057 g; 90.9%) as a pale yellow oil. MS (ESI): m/z = 268.2 [MC ₄ H ₈ +H] ⁺ .

BB7 1 -methyl -5-(4- hexahydropyridyl ) indazole hydrochloride to 4-(1-methyl-1H-indazol-5-yl) hexahydropyridine-1-carboxylic acid third butyl A solution of the ester (155 mg, 491 µmol) in dioxane (0.5 mL) was added 4 M HCl (614 µL, 2.46 mmol) in dioxane. The colorless suspension was stirred at room temperature for 3.5 hours. Ether (4 mL) was added and the suspension was filtered. The filter cake was washed with ether to obtain the desired product (0.107 g; 86.5%) as a light yellow solid. MS (ESI): m/z = 216.2 [M+-HCl+H] ⁺ .

Intermediate : a) 4-(1 -methylindazol- 5- yl ) hexahydropyridine- 1- carboxylic acid third butyl ester under argon to 4-(1-methyl-1H-indazole-5- Radical)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (160 mg, 511 µmol) in MeOH (3 mL) and EtOAc (1 mL) was added Pd-C 10% (16.3 mg, 15.3 µmol), and the suspension was stirred under a 1.7 bar hydrogen atmosphere for 2.5 hours. The solid was filtered off and the filtrate was evaporated to give the desired compound (0.156 g; 96.9%) as a colorless oil. MS (ESI): m/z = 316.3 [M+H] ⁺ . b) 4-(1 -methyl -1H- indazol- 5- yl )-3,6 -dihydropyridine- 1(2H) -carboxylic acid tert-butyl ester to 4-(((trifluoromethyl) (Sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (200 mg, 604 µmol, CAS RN 138647-49-1) in DME (3 mL) and 2 M Na ₂ CO ₃ aqueous solution (770 µL, 1.54 mmol) was added with palladium(II) acetate (2.71 mg, 12.1 µmol), triphenylphosphine (7.92 mg, 30.2 µmol) and 1-methyl-5-( 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-indazole (171 mg, 664 µmol, CAS RN 1235469-00-7 ), and the clear bilayer mixture was heated to 90°C for 2 hours. The reaction mixture was poured onto H2O and EtOAc, and the layers were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layer was dried over MgSO ₄ , filtered, treated with silica gel and evaporated. By silica gel chromatography, using a MPLC system on a 12 g column using n-heptane: EtOAc gradient (100: 0 to 0: 100) for dialysis to purify the compound, yielding the desired compound as a colorless solid (0.163 g; 86.2%). MS (ESI): m/z = 314.3 [M+H] ⁺ .

BB8 (E or Z)-2- phenyl- 3 -hexahydropyrazin- 1 -yl - prop -2 -enenitrile hydrochloride in 4 M HCl solution in dioxane (3.6 g, 3 mL, 98.7 mmol) treated (E or Z)-4-[2-cyano-2-phenyl-vinyl]hexahydropyrazine-1-carboxylic acid tert-butyl ester (300 mg, 951 µmol). The reaction mixture was stirred at room temperature for 15 h, and then concentrated in vacuo to give a light yellow solid (240 mg, 100%); MS (ESI): m/z = 214.2 [M+H] ⁺ .

Intermediate: (E or Z)-4-[2- cyano-2- phenyl- vinyl] hexahydropyrazine-1- carboxylic acid third butyl ester Ester (200 mg, 1.07 mmol, CAS RN 57260-71-6), 3-oxo-2-phenylpropionitrile (156 mg, 1.07 mmol, CAS RN 5841-70-3), and triacetoxy Sodium borohydride (228 mg, 1.07 mmol, CAS RN 56553-60-7) was dissolved in DCM (5 mL). The reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was washed with H ₂ O, NaHCO ₃ and brine. The organic phase was dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo to give a brown solid (300 mg). MS (ESI): m/z = 314.2 [M+H] ⁺ .

BB9 5- chloro- 1 -cyclopropyl- 3-(4- hexahydropyridyl ) indole hydrochloride to 4-(5-chloro-1-cyclopropyl-1H-indol-3-yl) hexa A mixture of tert-butyl hydropyridine-1-carboxylate (275.0 mg, 0.730 mmol) in EtOAc (5 mL) was added HCl/EtOAc (4M, 4 mL), and the mixture was stirred at 20°C for 3 hours. The mixture was concentrated, and the residue was diluted with H ₂ O (30 mL) and washed with EtOAc (10 mL×2). The aqueous layer was lyophilized to give the title compound (189.4 mg, 81.3%) as a pale yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.29-8.87 (m, 2H), 7.76 (d, J = 1.9 Hz, 1H), 7.53 (d, J = 8.7 Hz, 1H), 7.23-7.10 (m , 2H), 3.38-3.27 (m, 3H), 3.08-2.90 (m, 3H), 2.07-1.98 (m, 2H), 1.98-1.83 (m, 2H), 1.09-1.00 (m, 2H), 0.96 -0.88 (m, 2H). MS (ESI): m/z = 275.1 [M+H] ⁺ .

酸(153.92 mg, 1.79 mmol; CAS RN 411235-57-9)、於THF中之1 M NaHMDS溶液(3 mL, 2.99 mmol; CAS RN 1070-89-9)、DMAP (0.22 mL, 1.79 mmol)及乙酸銅(II)(270.22 mg, 1.49 mmol; CAS RN 142-71-2)於甲苯(25 mL)中之混合物在95℃下攪拌12 h (帶氧氣囊)。將混合物傾倒至H₂ O (20 mL)中並用EtOAc (50 mL × 3)萃取。將合併之有機層用鹽水(50 mL)洗滌，經Na₂ SO₄ 乾燥，過濾並在真空中濃縮。藉由急速矽膠管柱層析(100-200目)，使用PE : EtOAc之梯度(50 : 1至20 : 1)純化殘餘物，得到呈淺黃色油狀物之標題化合物(275 mg, 0.730 mmol, 49.1%)。MS (ESI): m/z = 275.1 [M-Boc+H]⁺ 。b) 4-(5- 氯 -1H- 吲哚 -3- 基 ) 六氫吡啶 -1- 甲酸第三丁基酯 將4-(5-氯-1H-吲哚-3-基)-3,6-二氫-2H-吡啶-1-甲酸第三丁基酯(1.003 g, 3.01 mmol)及氧化鉑(IV)(100.0 mg, 0.350 mmol; CAS RN 1314-15-4 )於AcOH (10.0 mL)及EtOH (20 mL)中之混合物在H₂ (1520 mm Hg)下在40℃下攪拌15 h。過濾該混合物且將濾液在真空下濃縮。使殘餘物與PE (50 mL)一起研磨並過濾。收集濾餅並在真空下乾燥，得到呈淺灰色固體之標題化合物(780 mg, 77.3%)。MS (ESI): m/z = 235.1 [M-Boc+H]⁺ 。 c) 4-(5- 氯 -1H- 吲哚 -3- 基 )-3,6- 二氫 -2H- 吡啶 -1- 甲酸第三丁基酯 向5-氯吲哚(1 g, 6.6 mmol; CAS RN 17422-32-1)於MeOH (20 mL)中之混合物添加4-側氧基六氫吡啶-1-甲酸第三丁基酯(1.97 g, 9.9 mmol; CAS RN 79099-07-3)。將混合物在20℃下攪拌1小時，且然後添加氫氧化鉀(1.48 g, 26.39 mmol)。將混合物在70℃下攪拌15 h。在真空下濃縮該混合物。使殘餘物與PE及EtOAc之混合物(5:1, 50 mL)一起研磨並過濾。收集濾餅並在真空下乾燥，得到呈淺黃色固體之標題化合物(2 g, 91.3%)。MS (ESI): m/z = 227.1 [M-C₄ H₈ +H]⁺ 。 Intermediate: a) 4- (5- chloro-1-cyclopropyl -1H- indol-3-yl) -piperidine-1-carboxylic acid butyl ester third 4- (5-Chloro -1H- indazol Indol-3-yl)hexahydropyridine-1-carboxylic acid tert-butyl ester (500 mg, 1.49 mmol), cyclopropyl

Acid (153.92 mg, 1.79 mmol; CAS RN 411235-57-9), 1 M NaHMDS solution in THF (3 mL, 2.99 mmol; CAS RN 1070-89-9), DMAP (0.22 mL, 1.79 mmol) and A mixture of copper (II) acetate (270.22 mg, 1.49 mmol; CAS RN 142-71-2) in toluene (25 mL) was stirred at 95°C for 12 h (aerobic balloon). The mixture was poured into H ₂ O (20 mL) and extracted with EtOAc (50 mL×3). The combined organic layer was washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (100-200 mesh) using a gradient of PE: EtOAc (50: 1 to 20: 1) to give the title compound (275 mg, 0.730 mmol) as a pale yellow oil , 49.1%). MS (ESI): m/z = 275.1 [M-Boc+H] ⁺ . b) tert-butyl 4-(5- chloro -1H- indol- 3 -yl ) hexahydropyridine- 1- carboxylate 4-(5-chloro-1H-indol-3-yl)-3, 6-Dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.003 g, 3.01 mmol) and platinum(IV) oxide (100.0 mg, 0.350 mmol; CAS RN 1314-15-4) in AcOH (10.0 mL ) And EtOH (20 mL) were stirred under H ₂ (1520 mm Hg) at 40° C. for 15 h. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was triturated with PE (50 mL) and filtered. The filter cake was collected and dried under vacuum to give the title compound (780 mg, 77.3%) as a light gray solid. MS (ESI): m/z = 235.1 [M-Boc+H] ⁺ . c) 4-(5- chloro -1H- indol- 3 -yl )-3,6 -dihydro -2H- pyridine- 1- carboxylic acid tert-butyl ester to 5-chloroindole (1 g, 6.6 mmol ; CAS RN 17422-32-1) in MeOH (20 mL) was added tert-butyl 4-oxohexahydropyridine-1-carboxylate (1.97 g, 9.9 mmol; CAS RN 79099-07-3 ). The mixture was stirred at 20°C for 1 hour, and then potassium hydroxide (1.48 g, 26.39 mmol) was added. The mixture was stirred at 70 °C for 15 h. The mixture was concentrated under vacuum. The residue was triturated with a mixture of PE and EtOAc (5:1, 50 mL) and filtered. The filter cake was collected and dried under vacuum to give the title compound (2 g, 91.3%) as a light yellow solid. MS (ESI): m/z = 227.1 [MC ₄ H ₈ +H] ⁺ .

BB10 5- chloro- 1-( oxetan- 3 -yl )-3-(4- hexahydropyridyl ) indole 4-[5-chloro-1-(oxetan-3-yl) -1H-Indol-3-yl]hexahydropyridine-1-carboxylic acid tert-butyl ester (1 g, 2.56 mmol) in DCM (20 mL) was added TFA (5.0 mL). The mixture was stirred at 20°C for 12 hours. The mixture was concentrated in vacuo and purified by preparative HPLC (0.1% FA and ACN in H ₂ O) to give the title compound (311.3 mg, 37.3%) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J = 1.8 Hz, 1H), 7.65 (s, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.17 (dd, J = 1.9 , 8.7 Hz, 1H), 5.73 (quin, J = 7.0 Hz, 1H), 5.01 (t, J = 7.2 Hz, 2H), 4.90 (t, J = 6.5 Hz, 2H), 3.38 (br d, J = 12.2 Hz, 2H), 3.14-3.00 (m, 3H), 2.07 (br d, J = 13.2 Hz, 2H), 1.96-1.78 (m, 2H). MS (ESI): m/z = 291.1 [M+H] ⁺ .

Intermediate: 4-(5-chloro-1-(oxetan-3-yl)-1H-indol-3-yl)hexahydropyridine-1-carboxylic acid tert-butyl ester at 0°C to 4 -(5-chloro-1H-indol-3-yl)hexahydropyridine-1-carboxylic acid tert-butyl ester (1 g, 2.99 mmol, BB9, intermediate step b) in DMF (20 mL) Added 60% NaH (143.35 mg, 3.58 mmol) in mineral oil. The mixture was stirred at 20°C for 1 hour, and then 4-tosylate oxetan-3-yl ester (1022.55 mg, 4.48 mmol; CAS RN 26156-48-9) was added, and the mixture was at 85°C Stir for 12 hours. The mixture was poured into H ₂ O (60 mL) and extracted with EtOAc (50 mL×3). The combined organic layer was washed with brine (50 mL), dried over Na ₂ SO ₄ and concentrated under vacuum to give the title compound (1.1 g, 2.81 mmol, 94.2%) as a light yellow solid. MS (ESI): m/z = 291.1 [M-Boc+H] ⁺ .

BB11 4-( bis (4- fluorophenyl ) methyl ) hexahydropyridinecarboxylic acid salt to 4-[bis(4-fluorophenyl)methylene]hexahydropyridine (700.0 mg, 1.75 mmol) in AcOH ( The solution in 50.0 mL) was added with Pd/C (1.0 g), the reaction was purged with hydrogen three times and stirred at 90°C (under a hydrogen balloon) for 48 hours. The reaction mixture was filtered and concentrated in vacuo. The crude product was purified by preparative HPLC (0.1% FA and MeCN in water) to give the title compound (263.5 mg, 32.1%) as a light gray solid. ¹ H NMR (DMSO-d6, 400MHz,) δ 8.39 (s, 1H), 7.45-7.37 (m, 4H), 7.15-7.07 (m, 4H), 3.68 (d, J = 11.2 Hz, 1H), 3.17 (br d, J = 12.3 Hz, 2H), 2.80-2.68 (m, 1H), 2.46 (br d, J = 11.2 Hz, 1H), 1.54-1.32 (m, 2H), 1.27-1.09 (m, 2H ). MS (ESI): m/z = 288.1 [M+H] ⁺ .

Intermediate: a) 4-[ bis (4- fluorophenyl ) methylene ] hexahydropyridine to bis(4-fluorophenyl)(hexahydropyridin-4-yl)methanol (900.0 mg, 2.59 mmol) in The solution in DCM (30 mL) was added TFA (10.0 mL), and the reaction mixture was stirred at 20° C. for 12 hours. The reaction mixture was concentrated in vacuo to give the crude title compound, which was used in the next step without further purification. MS (ESI): m/z = 286.1 [M+H] ⁺ . b) Bis (4- fluorophenyl )( hexahydropyridin- 4 -yl ) methanol A mixture of Mg (1.4 g, 58.29 mmol) and I ₂ (20.0 mg, 0.080 mmol) was suspended in THF (40 mL). 1-Bromo-4-fluorobenzene (1.0 g, 5.75 mmol, CAS RN 460-00-4) was added to the above yellow solution, and the reaction mixture was heated to 45°C until the solution became clear. Add another batch of 1-bromo-4-fluorobenzene (9.14 g, 52.54 mmol, CAS RN 460-00-4) (dissolved in 10 mL THF). The reaction mixture was stirred at 45°C for 30 min. N-BOC-hexahydropyridine-4-carboxylic acid ethyl ester (1.5 g, 5.83 mmol, CAS RN 142851-03-4) was added, and the reaction mixture was stirred at 80°C for 12 hours. The mixture was poured into saturated aqueous NH ₄ Cl (50 mL), the mixture was extracted twice with EtOAc (50 mL each time), and the combined organic layer was washed with water (30 mL × 2) and brine (30 mL), Na ₂ SO _{4 was} dried and concentrated in vacuo to give the title compound (900 mg, 38.2%). 1H NMR (400 MHz, DMSO-d6) δ 8.70 (br s, 1H), 7.57-7.47 (m, 4H), 7.12 (t, J = 8.8 Hz, 4H), 5.73 (s, 1H), 3.23 (br d, J = 12.3 Hz, 2H), 2.92-2.79 (m, 3H), 1.68-1.54 (m, 2H), 1.39 (br d, J = 13.6 Hz, 2H). MS (ESI): m/z = 304.1 [M+H] ⁺ .

BB12 5- chloro- 1-( oxetan- 3 -ylmethyl )-3-(4- hexahydropyridinyl ) indole 4-[5-chloro-1-(oxetan-3- (Tymethyl)indol-3-yl]hexahydropyridine-1-carboxylic acid tert-butyl ester (700.0 mg, 1.73 mmol) in DCM (20 mL) was added TFA (3.38 mL). The mixture was stirred at 20°C for 12 h. The mixture was concentrated under vacuum and purified by preparative HPLC (0.1% FA and ACN in H2O) to give the title compound (154.57 mg, 29.0%) as a pale yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.60 (br s, 1H), 7.71 (d, J = 1.7 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.33 (s, 1H) , 7.13 (dd, J = 1.8, 8.7 Hz, 1H), 4.59 (dd, J = 6.2, 7.6 Hz, 2H), 4.47-4.33 (m, 4H), 3.43-3.37 (m, 3H), 3.08-2.99 (m, 3H), 2.04 (d, J = 13.0 Hz, 2H), 1.89-1.76 (m, 2H). MS (ESI): m/z = 305.2 [M+H] ⁺ .

Intermediate: a) 4-[5- chlorine -1-( Oxetane -3- Methyl ) Indole -3- base ] Hexahydropyridine -1- Formic acid Tributyl ester To 4-(5-chloro-1H-indol-3-yl)hexahydropyridine-1-carboxylic acid tert-butyl ester (400.0 mg, 1.19 mmol, BB9, intermediate step b) at 0°C in DMF ( 8 mL) was added 60% NaH (57.34 mg, 2.39 mmol) in mineral oil. The mixture was stirred at 20°C for 1 hour. Then 4-tosylate oxetan-3-ylmethyl ester (434.16 mg, 1.79 mmol) was added, and the mixture was stirred at 85°C for 12 hours. Pour the mixture to H₂ O (60 mL) and extracted with EtOAc (50 mL × 3). The combined organic layer was washed with brine (50 mL), washed with Na₂ SO₄ Dry and concentrate in vacuo to give the title compound (629 mg, crude) as a yellow oil. MS (ESI):m/z = 305.0 [M-Boc+H]⁺ . b) 4- Oxetane tosylate -3- Methyl ester To a solution of 3-oxetane methanol (500.0 mg, 5.67 mmol; CAS RN 6246-06-6) in DCM (10 mL) was added TEA (1.19 mL, 8.51 mmol), DMAP (69.33 mg, 0.570 mmol ) And 4-toluene-1-sulfonyl chloride (1293.77 mg, 6.81 mmol; CAS RN 98-59-9). The mixture was stirred at 20°C for 6 hours. With EtOAc and saturated NH₄ A mixture of Cl aqueous solution (1:1, 20 mL) diluted the mixture. The mixture was extracted with EtOAc (40 mL×3). The combined organic layer was washed with brine, washed with Na₂ SO₄ Dry, filter and concentrate to give the title compound as a brown solid (1.25 g, 5.16 mmol, 78.7%). MS (ESI): m/z = 243.1 [M+H]⁺ .

BB13 1- (2 - ((tert-butyl-dimethyl-silicon based) oxy) ethyl) -5-chloro-3- (hexahydro-4-yl) lH-indole To a solution of 2- [5 -Chloro-3-(4-hexahydropyridyl)indol-1-yl]ethanol (600.0 mg, 1.39 mmol) in pyridine (5 mL) was added tert-butyldimethylchlorosilane (251.35 mg , 1.67 mmol; CAS RN 18162-48-6), and the mixture was stirred at 20°C for 12 hours. The mixture was poured into H ₂ O (10 mL) and extracted with EtOAc (20 mL×3). The combined organic layer was washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was triturated with PE (10 mL) and filtered. The filter cake was washed with PE (5 mL × 2), and the solid was collected and dried in vacuo to give the title compound (164.7 mg, 29.8%) as a pale yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.97 (br s, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.47 (d, J = 8.7 Hz, 1H), 7.20 (s, 1H) , 7.10 (dd, J = 1.8, 8.7 Hz, 1H), 4.22 (br t, J = 4.8 Hz, 2H), 3.84 (t, J = 4.9 Hz, 2H), 3.44-3.32 (m, 2H), 3.12 -2.94 (m, 3H), 2.08-1.96 (m, 2H), 1.95-1.81 (m, 2H), 0.73 (s, 9H), -0.24 (s, 6H). MS (ESI): m/z = 393.1 [M+H] ⁺ .

Intermediate: a) 2-[5- chloro- 3-(4- hexahydropyridyl ) indol- 1 -yl ] ethanol to 4-[5-chloro-1-(2-hydroxyethyl) indole- 3-yl]hexahydropyridine-1-carboxylic acid tert-butyl ester (1.1 g, 2.9 mmol) in EtOAc (10 mL) was added HCl/ETOAC (4M, 0.73 mL). The mixture was stirred at 20°C for 3 hours, and then concentrated in vacuo. The residue was diluted with DCM (20 mL) and washed with saturated aqueous NaHCO ₃ (10 mL). The aqueous layer was extracted with DCM: MeOH (5: 1 v/v; 20 mL × 3). The combined organic layer was dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuo to give the title compound (750 mg, 59.8%) as a pale yellow oil. MS (ESI): m/z = 279.1 [M+H] ⁺ . b) 4-[5- chloro- 1-(2- hydroxyethyl ) indol- 3 -yl ] hexahydropyridine- 1- carboxylic acid tert-butyl ester 4-(5-chloro-1H-indole- 3-yl)tert-butyl hexahydropyridine-1-carboxylate (1 g, 2.99 mmol, intermediate BB9, step b), 2-bromoethanol (0.32 mL, 4.48 mmol; CAS RN 540-51-2) A mixture of potassium hydroxide (335.12 mg, 5.97 mmol) in DMF (10 mL) was stirred at 100°C for 12 hours. The mixture was purified by preparative HPLC (0.1% ammonia in H2O and ACN) to give the title compound (1.1 g, 97.2%) as a light yellow oil. MS (ESI): m/z = 323.1 [MC ₄ H ₈ +H] ⁺ .

BB14a and BB14b (+)-4a,5,6,7,8,8a -hexahydro -4H- pyrido [4,3-b][1,4] oxazin- 3 -one and (-)- cis Formula- 4a,5,6,7,8,8a -hexahydro -4H- pyrido [4,3-b][1,4] oxazin- 3 -one by preparative chiral HPLC (ReprosilChiral NR tube Column), using EtOH (containing 0.05% NH ₄ OAc): n-heptane isocratic mixture (30: 70) separation of racemic-(4aR, 8aS)-hexahydro-2H-pyrido [4,3- b] The mirror isomer of [1,4]oxazine-3(4H)-one dihydrochloride (500 mg, 2.18 mmol, ChemBridge Corporation).

Mirror image isomer of the first leaching: (+)-cis-4a,5,6,7,8,8a-hexahydro-4H-pyrido[4,3-b][1,4]oxazine -3-one. Yellow solid (0.150 g; 44.0%). MS (ESI): m/z = 157.1 [M+H] ⁺ .

Mirror image isomer of the second leaching: (-)-cis-4a,5,6,7,8,8a-hexahydro-4H-pyrido[4,3-b][1,4]oxazine -3-one. Yellow solid (0.152 g; 44.6%). MS (ESI): m/z = 157.1 [M+H] ⁺ .

BB15a and BB15b (4aR,8aS)-3 - oxohexahydro -2H- pyrido [4,3-b][1,4] oxazine- 6(5H) -carboxylic acid 4- nitrophenyl ester ( BB15a) and (4aS,8aR)-3 - oxohexahydro -2H- pyrido [4,3-b][1,4] oxazine- 6(5H) -carboxylic acid 4- nitrophenyl ester ( BB15b) Racemic- (4aR,8aS)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; dihydrochloride at 0℃ (4.5 g, 19.6 mmol, BB1) suspension in anhydrous DCM (125 mL) was added DIPEA (6.35 g, 8.58 mL, 49.1 mmol) followed by 4-nitrophenyl chloroformate (4.35 g, 21.6 mmol) ). The reaction mixture was stirred at 0 °C for 10 min and at room temperature for 2 h. The crude reaction was diluted with DCM and transferred to a separatory funnel for extraction with saturated aqueous Na ₂ CO ₃ solution. The organic phase was collected and the aqueous phase was back extracted with DCM. The combined organic phase was dried over Na ₂ SO ₄ and evaporated to dryness, yielding 6.62 g of crude racemic product (BB7) as a yellow solid. The crude material was directly subjected to chiral SFC separation to produce the mirror isomer BB15b (2.72 g, the second eluted mirror isomer) as a yellow solid and the mirror isomer BB15a which was a light beige solid but contaminated with BB15b 3.25 g, the first mirror image isomer). A further SFC chiral separation was performed to produce 2.71 g of BB15a. MS (ESI) of the two mirror isomers: m/z = 322.2 [M+H] ⁺ .

BB16 3-(4- fluorophenyl )-3-( hexahydropyridin- 4 -yl ) propan- 1- ol hydrochloride will 4-(1-(4-fluorophenyl)-3-hydroxypropyl) A solution of tert-butyl hexahydropyridine-1-carboxylate (119 mg, 353 µmol, BB5, intermediate b) in 2 M HCl (in diethyl ether) (1.76 mL, 3.52 mmol) was stirred at room temperature 4.5 h, after which another batch of 2 M HCl in diethyl ether (1.76 mL, 3.53 mmol) was added. Continue stirring overnight at room temperature. The suspension was homogenized in ice-cold ultrasound and filtered. The filter cake was washed with a small volume of diethyl ether to obtain the desired compound (0.067 g; 69.4%) as a colorless solid. MS (ESI): m/z = 238.2 [M+H] ⁺ .

BB17 4-[1-[4-( trifluoromethyl ) phenyl ] ethyl ] hexahydropyridine formate will 4-[1-[4-(trifluoromethyl)phenyl]ethyl]hexahydro A solution of tert-butyl pyridine-1-carboxylate (1.5 g, 4.2 mmol) in a mixture of HCl/dioxane (50.0 mL, 1/1 v/v) was stirred at 20°C for 2 h. The mixture was concentrated and the residue was purified by preparative HPLC (FA) and lyophilized to obtain the desired compound (838.4 mg, 77.1%) as a pale yellow oil. MS (ESI): m/z = 258.1 [M+H] ⁺ .

Intermediate : a) 4-[1-[4-( trifluoromethyl ) phenyl ] ethyl ] hexahydropyridine- 1- carboxylic acid tertiary butyl ester 4-[1-[4-(trifluoromethyl Group) phenyl] vinyl] hexahydropyridine-1-carboxylic acid tert-butyl ester (2.0 g, 5.63 mmol) in EtOAc (100 mL) was added Pd/C (1.0 g, 5.63 mmol), the mixture Stir for 12 h at 20°C under H ₂ atmosphere (balloon). The mixture was filtered and the filtrate was concentrated to obtain the desired compound (1.8 g, 89.5%) as a colorless oil. MS (ESI): m/z = 302.2 [MC ₄ H ₈ +H] ⁺ . b) 4-[1-[4-( Trifluoromethyl ) phenyl ] vinyl ] hexahydropyridine- 1- carboxylic acid tert-butyl ester at 0°C to methyltriphenylphosphonium bromide (10.0 g , 27.98 mmol, CAS RN 1779-49-3) solution in THF (250 mL) was added dropwise lithium bis(trimethylsilyl)amide (41.97 mL, 41.97 mmol) in THF, and the mixture Stir at 0 °C for 1 h. Then 4-[4-(trifluoromethyl)benzyl]hexahydropyridine-1-carboxylic acid tert-butyl ester (10.0 g, 27.98 mmol, CAS RN 725229) in THF (50 mL) was added dropwise -27-6), and the mixture was heated to 20 °C over 2 h. The mixture was poured into aqueous NH ₄ Cl solution (500 mL) and extracted three times with EtOAc (200 mL each time). The organic phase was washed with brine and dried over Na ₂ SO ₄ , filtered and the filtrate was purified by silica gel column (PE: EtOAc = 20: 1) to provide the desired compound as a light yellow oil. (5.1 g, 51.3%). 1H NMR (400 MHz, chloroform-d) δ = 7.61 (d, J=8.2 Hz, 2H), 7.44 (d, J=8.1 Hz, 2H), 5.25 (s, 1H), 5.13 (s, 1H), 4.27-4.14 (m, 2H), 2.77 (br t, J=12.3 Hz, 2H), 2.58 (br t, J=11.6 Hz, 1H), 1.78 (br d, J=13.0 Hz, 2H), 1.48 ( s, 9H), 1.43-1.32 (m, 2H). .

BB18 6- chloro- 1 -methyl- 3-(4- hexahydropyridyl ) indazole makes 1-[4-(6-chloro-1-methyl-indazol-3-yl)-1-hexahydro The pyridyl]ethanone mixture (3.95 g, 14 mmol) was refluxed in 25% aqueous HCl (25.75 mL) for 4 h. After cooling to room temperature, the mixture was basified using concentrated aqueous NaOH. The aqueous layer was extracted twice with DCM. The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to obtain the desired compound (3.6 g, 98.2%) as a light red oil. MS (ESI): m/z = 250.2 [M+H] ⁺ . This compound was used in the next step without further purification.

Intermediate: 1-[4-(6- chloro- 1 -methyl - indazol- 3 -yl )-1 -hexahydropyridyl ] ethanone in a sealed tube will 1-[4-(4-chloro- 2-fluoro-benzyl)-1-hexahydropyridyl]ethanone (3.9 g, 14 mmol; Novel Chemical Solutions) was mixed with methylhydrazine (0.94 mL, 18 mmol), and the mixture was at 120°C Heat for 16 h. After cooling, the mixture was basified using concentrated aqueous NaHCO ₃ solution. The aqueous layer was extracted twice with DCM. The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to provide the desired compound (3.97 g, 100%) as a yellow oil. MS (ESI): m/z = 292.3 [M+H] ⁺ . This compound was used in the next step without further purification.

BB19 2-(4- fluorophenyl )-2-( hexahydropyridin- 4 -yl ) acetonitrile hydrochloride is similar to BB16, from 4-(cyano(4-fluorophenyl)methyl)hexahydropyridine- 3-Butyl 1-formate (MFCD28112711, A Chemtek) gave the product as a pale yellow solid. (0.101 g; 87.1%). MS (ESI): m/z = 219.1 [M+H] ⁺ .

BB20 4-((4- fluorophenyl )(2,2,2- trifluoroethoxy ) methyl ) hexahydropyridine hydrochloride is similar to BB16, from 4-((4-fluorophenyl)(2 , 2,2-trifluoroethoxy)methyl)hexahydropyridine-1-carboxylic acid tert-butyl ester gave the product as a colorless foam (0.151 g; 100.0%). MS (ESI): m/z = 292.2 [M+H] ⁺ .

Intermediate: 4-((4- fluorophenyl )(2,2,2- trifluoroethoxy ) methyl ) hexahydropyridine- 1- carboxylic acid third butyl ester to tri-n-butylphosphine (262 mg, 319 µL, 1.29 mmol) and azodimethyl dihydropyridine (326 mg, 1.29 mmol) in toluene (10 mL) yellow solution was added 4-((4-fluorophenyl)(hydroxy)methyl Yl) hexahydropyridine-1-carboxylic acid tert-butyl ester (200 mg, 646 µmol, CAS RN 160296-41-3), and the mixture was stirred at room temperature for 10 min. Add 2,2,2-trifluoroethanol (711 mg, 514 µL, 7.11 mmol) to obtain a suspension. After heating under reflux for 20 h, the reaction mixture was cooled to room temperature. Silicone was added and the mixture was evaporated. The compound was purified by silica gel chromatography using a MPLC (ISCO) system using a gradient of n-heptane: EtOAc (100:0 to 50:50) on a 12 g column to obtain the desired colorless oil. Compound (0.180 g; 71.1%). MS (ESI): m/z = 391.1 [M+H] ⁺ .

BB21 5-(2-(4- fluorophenyl )-2-( hexahydropyridin- 4 -yl ) ethyl )-3 -methyl -1,2,4 -oxadiazole hydrochloride is similar to BB16, From 4-(1-(4-fluorophenyl)-2-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)hexahydropyridine-1-carboxylic acid tert-butyl Ester (0.051 g; 98.3%) gave the product as a colorless solid. MS (ESI): m/z = 290.2 [M+H] ⁺ .

Intermediate: a) 4-(1-(4- fluorophenyl )-2-(3- methyl -1,2,4 -oxadiazol- 5- yl ) ethyl ) hexahydropyridine- 1- carboxylic acid Tertiary butyl ester to 4-(3-ethoxy-1-(4-fluorophenyl)-3- pendoxypropyl)hexahydropyridine-1-carboxylic acid tert-butyl ester (100 mg, 264 µmol) and (Z)-N'-hydroxyacetamidine (39 mg, 527 µmol) in toluene (2.5 mL) was added K ₂ CO ₃ (72.8 mg, 527 µmol), and the reaction mixture was at 130 °C Stir for 14 days. The reaction was not over, so (Z)-N'-hydroxyacetamidine (39 mg, 527 µmol) and K ₂ CO ₃ (72.8 mg, 527 µmol) were added, and the RM was stirred at 130°C over the weekend. The reaction mixture was poured onto saturated aqueous NH ₄ Cl and EtOAc, and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layer was dried over MgSO ₄ , filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography using a MPLC system on a 4 g column using a gradient of n-heptane:EtOAc (100:0 to 0:100) to obtain the desired compound as a colorless solid. MS (ESI): m/z = 290.3 [M-Boc+H] ⁺ . b) 4-(3- ethoxy- 1-(4- fluorophenyl )-3 -oxopropyl ) hexahydropyridine- 1- carboxylic acid tert-butyl ester in a 25 mL round bottom flask. (E)-4-(3-ethoxy-1-(4-fluorophenyl)-3-oxoprop-1-en-1-yl)hexahydropyridine-1-carboxylic acid tert-butyl ester (1.747 g, 4.63 mmol) was combined with EtOAc (17.1 mL) to give a colorless solution. Pd/C 10% (175 mg, 4.63 mmol) was added under argon. The suspension was stirred under a hydrogen atmosphere of 1.5 bar for 4 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The compound was purified by silica gel chromatography using a MPLC (ISCO) system on a 24 g column using a gradient of n-heptane: EtOAc (100:0 to 50:50) to obtain the desired colorless oil. Compound (1.22 g; 69.8%). MS (ESI): m/z = 280 [M-Boc+H] ⁺ . c) (E)-4-(3- ethoxy- 1-(4- fluorophenyl )-3 -oxoprop- 1 -en- 1 -yl ) hexahydropyridine- 1- carboxylic acid tert -butyl Ethyl ester to a solution of ethyl 2-(diethoxyphosphonoyl)acetate (2.1 g, 1.86 mL, 9.36 mmol) in 1,4-dioxane (9.73 mL) was added dropwise in hexane 1.0 M LiHMDS (15 mL, 15 mmol), and the solution was stirred for 15 min. Dissolve 3-(4-fluorobenzyl)hexahydropyridine-1-carboxylic acid tert-butyl ester (2.878 g, 9.36 mmol, CAS RN 160296- in 1,4-dioxane (9.73 mL) 40-2) Add dropwise to the mixture and continue stirring under reflux for more than two days. The reaction mixture was poured onto saturated aqueous NH ₄ Cl and EtOAc, and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layer was washed once with water, dried over MgSO ₄ , filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography using a MPLC system on a 40 g column using a gradient of n-heptane: EtOAc (100:0 to 50:50) to obtain the desired compound as a colorless liquid (1.74 g, 49.4%). MS (ESI): m/z = 278.2 [M-Boc+H] ⁺ .

BB22 4-(1-(4-( trifluoromethyl ) phenyl ) cyclopropyl ) hexahydropyridine formate 4-[1-[4-(trifluoromethyl)phenyl]cyclopropyl] A solution of tert-butyl hexahydropyridine-1-carboxylate (250.0 mg, 0.680 mmol) in DCM (5 mL) was added TFA (1.0 mL, 0.680 mmol), and the mixture was stirred at 20° C. for 16 h. The mixture was concentrated and the residue was purified by preparative HPLC (FA) to give the desired compound (181 mg, 81.5%) as a yellow oil. MS (ESI): m/z = 270.1 [M+H] ⁺ .

Intermediate: a) 4-[1-[4-( trifluoromethyl ) phenyl ] cyclopropyl ] hexahydropyridine- 1- carboxylic acid tert-butyl ester at 0°C to 4-[2,2- Dibromo-1-[4-(trifluoromethyl)phenyl]cyclopropyl]hexahydropyridine-1-carboxylic acid tert-butyl ester (800.0 mg, 1.52 mmol) and titanium(IV) isopropoxide (862.56 mg, 3.03 mmol) in THF (30 mL) was added dropwise a 3 M EtMgBr solution (5.06 mL, 15.17 mmol) in THF. The mixture was warmed to 20°C over 16 h. The mixture was poured into NH ₄ Cl (100 mL aqueous solution) and extracted three times with EtOAc (30 mL each time). The organic phase was washed with brine and dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated. The residue was purified by reverse phase flash chromatography (FA) to provide the desired compound (250 mg, 44.6%) as a pale yellow oil. MS (ESI): m/z = 314.1 [MC ₄ H ₈ +H] ⁺ . b) 4-[2,2 -dibromo- 1-[4-( trifluoromethyl ) phenyl ] cyclopropyl ] hexahydropyridine- 1- carboxylic acid tertiary butyl ester 4-[1-[4 -(Trifluoromethyl)phenyl]vinyl]hexahydropyridine-1-carboxylic acid tert-butyl ester (1.2 g, 3.38 mmol, BB17, intermediate b), bromoform (2.56 g, 10.13 mmol, CAS RN 75-25-2) and cetyltrimethylammonium bromide (0.37 g, 1.01 mmol, CAS RN 57-09-0) in DCM (10 mL) vigorously stirred the mixture was added dropwise 50% aqueous NaOH ( 1.35 mL, 16.88 mmol). The reaction mixture was vigorously stirred at 50 °C for 16 h, and then H 2 O (20 mL) was added. The organic phase was separated and the aqueous phase was extracted three times with DCM (10 mL each time). The combined organic phase was washed with H 2 O, 2% HCl and brine and dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by preparative TLC (PE: EtOAc = 20: 1) to give the desired compound (900 mg, 50.5%) as a colorless oil. MS (ESI): m/z = 471.9 [MC ₄ H ₈ +H] ⁺ .

BB23 4-(1-(4- fluorophenyl )-2-(2,2,2- trifluoroethoxy ) ethyl ) hexahydropyridine hydrochloride is similar to BB16, from 4-(1-(4 -Fluorophenyl)-2-(2,2,2-trifluoroethoxy)ethyl)hexahydropyridine-1-carboxylic acid tert-butyl ester to obtain the product as a colorless foam (0.173 g; 97.7% ). MS (ESI): m/z = 306.2 [M+H] ⁺ .

Intermediate: 4-(1-(4- fluorophenyl )-2-(2,2,2- trifluoroethoxy ) ethyl ) hexahydropyridine- 1- carboxylic acid tert-butyl ester A yellow solution of butylphosphine (273 mg, 333 µL, 1.35 mmol) and azodimethine (340 mg, 1.35 mmol) in toluene (11.1 mL) was added 4-(1-(4-fluoro Phenyl)-2-hydroxyethyl) hexahydropyridine-1-carboxylic acid tert-butyl ester (218 mg, 674 µmol, BB5, intermediate b), and the mixture was stirred at room temperature for 10 minutes. Add 2,2,2-trifluoroethanol (742 mg, 536 µL, 7.42 mmol) to obtain a suspension. Upon heating to 65°C again, a yellow solution was formed. After heating under reflux for 17 hours, the reaction mixture was cooled to room temperature. Silicone was added and the mixture was evaporated. The compound was purified by silica gel chromatography using a MPLC (ISCO) system using a gradient of n-heptane: EtOAc (100:0 to 50:50) on a 12 g column to obtain the desired colorless oil. Compound (0.211 g; 77.2%). MS (ESI): m/z = 350.1 [MC ₄ H ₈ +H] ⁺ .

BB24 3-(1-(4-( trifluoromethyl ) phenyl ) ethyl ) azetidine formate is similar to BB22 from 3-[1-[4-(trifluoromethyl)phenyl] Ethyl] azetidine-1-carboxylic acid tert-butyl ester gave the product as a pale yellow oil (151.5 mg, 27.4%). MS (ESI): m/z = 230.1 [M+H] ⁺ .

Intermediate: a) 3-[1-[4-( Trifluoromethyl ) phenyl ] ethyl ] azetidine- 1- carboxylic acid tert-butyl ester is similar to BB17 intermediate a from 3-[1 -[4-(Trifluoromethyl)phenyl]vinyl]azetidine-1-carboxylic acid tert-butyl ester gave the product as a colorless oil (1 g, 99.4%). MS (ESI): m/z = 274.0 [MC ₄ H ₈ +H] ⁺ . b) 3-[1-[4-( Trifluoromethyl ) phenyl ] vinyl ] azetidine- 1- carboxylic acid tert-butyl ester at 0°C to methyltriphenylphosphonium bromide ( 1952.56 mg, 5.47 mmol, CAS RN 1779-49-3) solution in THF (25 mL) was added dropwise bis(trimethylsilyl) lithium amide/THF (9.11 mL, 9.11 mmol), the mixture was added Stir at 0°C for 1 h, then add 3-[4-(trifluoromethyl)benzyl]azetidine-1-carboxylic acid tert-butyl ester in THF (5 mL) dropwise ( 1500.0 mg, 4.55 mmol, MFCD24368873, FCH group), the mixture was heated to 20 ℃ for 2 h. The mixture was poured into NH ₄ Cl aqueous solution (100 mL) and extracted three times with EtOAc (50 mL each time), the organic phase was washed with brine and dried over Na ₂ SO ₄ , filtered and passed through a silica gel column (PE: EtOAc = 20:1) The filtrate was purified to obtain the desired compound (1000 mg, 67.0%) as a pale yellow oil. 1H NMR (400 MHz, chloroform-d) δ = 7.61 (d, J=8.1 Hz, 2H), 7.42 (d, J=8.1 Hz, 2H), 5.61 (s, 1H), 5.32 (s, 1H), 4.20 (t, J=8.4 Hz, 2H), 3.89 (br s, 2H), 3.83-3.73 (m, 1H), 1.46 (s, 9H).

BB25 5-((4- fluorophenyl )( hexahydropyridin- 4 -yl ) methyl )-3-( trifluoromethyl )-1,2,4 -oxadiazole hydrochloride is similar to BB16, from 4-((4-fluorophenyl)(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)hexahydropyridine-1-carboxylic acid third butyl ester was obtained Product as a colorless solid (0.119 g; 90.1%). MS (ESI): m/z = 330.2 [M+H] ⁺ .

Intermediate: 4-((4- fluorophenyl )(3-( trifluoromethyl )-1,2,4 -oxadiazol- 5- yl ) methyl ) hexahydropyridine- 1- carboxylic acid third butyl Ester to 2-(1-(third butoxycarbonyl)hexahydropyridin-4-yl)-2-(4-fluorophenyl)acetic acid (250 mg, 741 µmol, MFCD17214722, A Chemtek) in DMF ( 2 mL) of the solution was added CDI (120 mg, 741 µmol), and the mixture was stirred at room temperature for 30 minutes. To the clear solution was added a solution of (Z)-2,2,2-trifluoro-N'-hydroxyacetamidine (94.9 mg, 741 µmol) in DMF (0.5 mL), and stirring was continued at room temperature for 1 hour. The reaction mixture was heated in the microwave at 120°C for 30 minutes and then at 150°C for 30 minutes. The reaction mixture was poured onto water and EtOAc, and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layer was washed twice with water, dried over MgSO ₄ , filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography using a MPLC system on a 12 g column using a gradient of n-heptane: EtOAc (100:0 to 0:100) to provide the desired compound (0.155) as a colorless foam g; 48.7%). MS (ESI): m/z = 428.3 [MH] ^- .

BB26 (4aR,8aS)-6-[3-[(4- fluorophenyl )-(2,2,2- trifluoroethoxy ) methyl ] azetidine- 1- carbonyl ]-4, 4a,5,7,8,8a -hexahydropyrido [4,3-b][1,4] oxazin- 3 -one This product is similar to method A4, using 3-[(4-fluorophenyl )-(2,2,2-trifluoroethoxy)methyl]azetidine 2,2,2-trifluoroacetate to obtain the desired product as a white solid. MS (ESI): m/z = 446.2 [MC ₄ H ₈ +H] ⁺ . The product was used in the next step without further purification.

Intermediate: a) 3-[(4- fluorophenyl )-(2,2,2- trifluoroethoxy ) methyl ] azetidine 2,2,2- trifluoroacetate to 3- [(4-fluorophenyl)-(2,2,2-trifluoroethoxy)methyl]azetidine-1-carboxylic acid tert-butyl ester (1000.0 mg, 2.75 mmol) in DCM (20 mL) was added TFA (2.0 mL, 2.75 mmol), and the mixture was stirred at 20°C for 12 h. The mixture was concentrated and the residue was purified by preparative HPLC (TFA) to obtain the desired product (608.8 mg, 57.6%) as an off-white solid. MS (ESI): m/z = 264.1 [M+H] ⁺ . b) 3-[(4- fluorophenyl )-(2,2,2- trifluoroethoxy ) methyl ] azetidine- 1- carboxylic acid tertiary butyl ester 3-[(4- (Fluorophenyl)-hydroxy-methyl]azetidine-1-carboxylic acid tert-butyl ester (3000.0 mg, 10.66 mmol), 2,2,2-trifluoroethanol (1.55 mL, 21.33 mmol) and tri A solution of phenylphosphine (4195.52 mg, 16 mmol) in THF (50 mL) was added diisopropyl azodicarboxylate (3.15 mL, 16 mmol), and the mixture was stirred at 80° C. for 12 h. The mixture was concentrated and the residue was purified by reverse phase flash chromatography (FA) to give the desired product (1 g, 25.8%) as a yellow oil. MS (ESI): m/z = 308.1 [MC ₄ H ₈ +H] ⁺ . c) 3-[(4- fluorophenyl ) -hydroxy - methyl ] azetidine- 1- carboxylic acid tert-butyl ester to 3-(4-fluorobenzyl)azetidine- A solution of tert-butyl 1-carboxylate (2 g, 7.16 mmol, MFCD24368873, FCH group) in MeOH (30 mL) was added NaBH4 (541.33 mg, 14.32 mmol), and the mixture was stirred at 20°C for 1 h. The mixture was concentrated and dissolved in EtOAc (100 mL), washed with NH ₄ Cl aqueous solution and brine, dried over Na ₂ SO ₄ and concentrated to give the desired product (2 mg, 99.3%) as a light yellow oil. The compound was used in the next step without any further purification.

BB27 (4aR,8aS)-6-[3-[1-(2- chloro- 4- fluoro - phenyl ) ethoxy ] azetidine- 1- carbonyl ]-4,4a,5,7, 8,8a -hexahydropyrido [4,3-b][1,4] oxazin- 3 -one This product is similar to method A4, using 3-[1-(2-chloro-4-fluoro-benzene Yl)ethoxy]azetidine 2,2,2-trifluoroacetate to obtain the desired product (230 mg, 59.8%) as an off-white solid. MS (ESI): m/z = 412.2 [M+H] ⁺ .

Intermediate: a) 3-[1-(2- chloro- 4- fluoro - phenyl ) ethoxy ] azetidine 2,2,2- trifluoroacetate This product is similar to BB26 intermediate a , Using 3-[1-(2-chloro-4-fluoro-phenyl)ethoxy]azetidine-1-carboxylic acid tert-butyl ester to give the desired product as a pale yellow gum (1.4 g, 67.2%). MS (ESI): m/z = 230.1 [M+H] ⁺ . b) 3-[1-(2- chloro- 4- fluoro - phenyl ) ethoxy ] azetidine- 1- carboxylic acid tert-butyl ester at 0 ℃ to 3-hydroxyazetidine Sodium hydride (1.54 g, 38.53 mmol) was added to a mixture of tert-butyl-1-carboxylate (5.34 g, 30.82 mmol, CAS RN 141699-55-0) in DMF (60 mL). The mixture was stirred at 20°C for 1 h. Then 1-(1-bromoethyl)-2-chloro-4-fluoro-benzene (6.1 g, 25.68 mmol, CAS RN 1341821-29-1) was added, and the mixture was stirred at 20°C for 12 h. The mixture was poured into ice water (200 mL) and extracted three times with EtOAc (100 mL each time). The combined organic layer was washed with brine (100 ml), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated. The residue was purified by preparative HPLC (FA) and concentrated under vacuum to give the desired product (2 g, 23.6%) as a pale yellow oil. MS (ESI): m/z = 230 [M+H-Boc] ⁺ .

BB28 3-(2- chloro- [1,1'- biphenyl ]-4 -yl ) azetidine 4 -toluenesulfonate to 3-(2-chloro-[1,1'-biphenyl] -4-yl)azetidine-1-carboxylic acid tert-butyl ester (60 mg, 174 µmol) in EtOAc (2 mL) was added 4-toluenesulfonic acid hydrate (39.8 mg, 209 µmol) , And the mixture was heated under reflux for 1 hour. The clear colorless solution was evaporated to obtain the desired product (0.10 g; 100%) as a colorless solid. MS (ESI): m/z = 244.2 [M+H] ⁺ .

酸(CAS RN 98-80-6)及3-(4-溴-3-氯苯基)氮雜環丁烷-1-甲酸第三丁基酯(CAS RN 2222937-56-4)獲得呈無色固體之產物。MS (ESI): m/z = 288.2 [M-C₄ H₈ +H]⁺ 。 Intermediate: 3-(2- chloro- [1,1'- biphenyl ]-4 -yl ) azetidine- 1- carboxylic acid tert-butyl ester Similar to method A5, from phenyl

Acid (CAS RN 98-80-6) and tert-butyl 3-(4-bromo-3-chlorophenyl)azetidine-1-carboxylate (CAS RN 2222937-56-4) were obtained as colorless Solid product. MS (ESI): m/z = 288.2 [MC ₄ H ₈ +H] ⁺ .

BB29 3-(4- bromo- 3- chlorophenyl ) azetidine 4 -toluenesulfonate is similar to BB28, from 3-(4-bromo-3-chlorophenyl)azetidine-1 -Tert-butyl formate (CAS RN 2222937-56-4) gives the product as a colorless solid. MS (ESI): 248.1 [M+H] ⁺ .

BB30 3-(3- bromophenyl ) azetidine 4 -toluenesulfonate is similar to BB28, from tert-butyl 3-(3-bromophenyl)azetidine-1-carboxylate ( CAS RN 1203681-54-2) to obtain the product as a colorless solid. MS (ESI): 212.1 [M+H] ⁺ .

BB31 3-(4 -tert-butylphenyl ) azetidine ; 4 -toluenesulfonic acid is similar to BB28, from 3-(4-(tert-butyl)phenyl)azetidine-1 -Tert-butyl formate (CAS RN 1629889-13-9) gives the product as a colorless solid. MS (ESI): 190.2 [M+H] ⁺ .

BB32 5-( azetidin- 3 -yl )-2 -chloropyridine 4 -toluenesulfonate is similar to BB28, from 3-(6-chloropyridin-3-yl)azetidine-1-carboxylic acid The third butyl ester (CAS RN 870689-19-3) gave the product as a colorless solid. MS (ESI): 169.1 [M+H] ⁺ .

BB33 3-(4-( trifluoromethyl ) phenyl ) azetidine 4 -toluenesulfonate is similar to BB28, from 3-(4-(trifluoromethyl)phenyl)azetidine The tert-butyl-1-carboxylate (CAS RN 1638255-66-9) gave the product as a colorless solid. MS (ESI): 202.2 [M+H] ⁺ .

BB34 3-((1,1,1- trifluoro -2 -methylpropan -2- yl ) oxy ) azetidine hydrochloride to 1-diphenylmethyl-3-((1,1 , 1-trifluoro-2-methylpropan-2-yl)oxy)azetidine (114 mg, 326 µmol) in ethanol (0.5 mL) and EtOAc (0.5 mL) was added to H ₂ 1 M HCl in O (326 µL, 326 µmol) and Pd/C 10% (20 mg, 326 µmol), and the mixture was stirred under a 1.7 bar hydrogen atmosphere for 5 h. The suspension was filtered through a microfilter and the filtrate was evaporated to obtain the desired compound (0.105 g) as a colorless amorphous. MS (ESI): m/z = 184.2 [M+H] ⁺ . It was used in the next step without further purification.

Intermediate: benzhydryl- 3-((1,1,1- trifluoro -2 -methylpropan -2- yl ) oxy ) azetidine under argon to 1,1,1-tris A solution of fluoro-2-methyl-propan-2-ol (807 mg, 690 µL, 6.3 mmol, CAS RN 507-52-8) in DMF (5 mL) was added to 60% sodium hydride in mineral oil ( 252 mg, 6.3 mmol), and the mixture was stirred at room temperature for 30 minutes. After adding (1-diphenylmethylazetidin-3-yl) methanesulfonate (1 g, 3.15 mmol, CAS RN 33301-41-6), the reaction mixture was heated in a microwave oven at 130°C 60 minutes. The reaction mixture was poured onto water and EtOAc, and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layer was washed once with water, dried over MgSO ₄ , filtered, treated with silica gel and evaporated. By silica gel chromatography, using a MPLC system on a 12 g column using n-heptane: EtOAc gradient (100: 0 to 50: 50) for dialysis to purify the compound, yielding the desired compound as a yellow solid (0.324 g; 29.4%). MS (ESI): m/z = 350.3 [M+H] ⁺ .

BB35 3-(4-(1,1 -difluoroethyl ) phenyl ) azetidine 4 -toluenesulfonate is similar to BB28, from 3-(4-(1,1-difluoroethyl) Phenyl) azetidine-1-carboxylic acid tert-butyl ester gave the product as a colorless solid (0.050 g; 35.9%). MS (ESI): m/z = 198.2 [M+H] ⁺ .

Intermediate: 3-(4-(1,1 -difluoroethyl ) phenyl ) azetidine- 1- carboxylic acid tert-butyl ester at room temperature to 2-(4-(1,1- (Difluoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (568 mg, 2.12 mmol, CAS RN 1000994-94-4) To a stirred suspension in -propanol (1.5 mL) was added 3-iodoazetidine-1-carboxylic acid tert-butyl ester (300 mg, 1.06 mmol, CAS RN 254454-54-1) in 2-propanol Solution in alcohol (1.5 mL) to get a solution. To the mixture was added racemic-(1R,2R)-2-aminocyclohexan-1-ol (7.32 mg, 63.6 µmol, CAS RN 13374-31-7), nickel(II) iodide (19.9 mg, 63.6 µmol) and sodium bis(trimethylsilyl)amide (1.06 mL, 2.12 mmol). The mixture was heated in a microwave oven at 100°C for 30 minutes. The reaction mixture was poured onto water and EtOAc, and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layer was dried over MgSO ₄ , filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography using a MPLC system on a 4 g column using a gradient of n-heptane: EtOAc (100:0 to 70:30) to provide the desired compound as a colorless oil (0.0112 g; 35.5%). MS (ESI): m/z = 242.2 [MC ₄ H ₈ +H] ⁺ .

BB36 5-(4-( azetidin- 3 -yl ) phenyl )-1 -methyl -1H- pyrazole 4 -toluenesulfonate is similar to BB28, from 3-(4-(1-methyl -1H-pyrazol-5-yl)phenyl)azetidine-1-carboxylic acid tert-butyl ester gave the product as a light brown gum. MS (ESI): m/z = 214.1 [M+H] ⁺ . The product was used in the next step without further purification.

酸(CAS RN 1487353-57-0)獲得呈淺棕色膠狀物之產物。MS (ESI): m/z = 314.3 [M+H]⁺ 。產物不經進一步純化即用於下一步驟中。 Intermediate: 3-(4-(1 -methyl -1H- pyrazol- 5- yl ) phenyl ) azetidine- 1- carboxylic acid tert-butyl ester is similar to BB35 intermediate, from (4- (1-methyl-1H-pyrazol-5-yl)phenyl)

Acid (CAS RN 1487353-57-0) gave the product as a light brown gum. MS (ESI): m/z = 314.3 [M+H] ⁺ . The product was used in the next step without further purification.

BB37 3-[4-(2,2,2- trifluoroethoxy ) phenyl ] azetidine trifluoroacetate is similar to BB26 intermediate a, from 3-[4-(2,2,2 -Trifluoroethoxy)phenyl]azetidine-1-carboxylic acid tert-butyl ester to obtain the product as a pale yellow oil. MS (ESI): m/z = 232.1 [M+H] ⁺ . The product was used in the next step without further purification.

Intermediate: 3-[4-(2,2,2- Trifluoroethoxy ) phenyl ] azetidine- 1- carboxylic acid tert-butyl ester to 1-bromo-4-(2,2, 2-trifluoroethoxy)benzene (0.45 g, 1.77 mmol, CAS RN 106854-77-7), 1-BOC-3-iodoazetidine (0.5 g, 1.77 mmol, CAS RN 254454-54- 1), 1,10-phenanthroline (63.65 mg, 0.350 mmol, CAS RN 5144-89-8), NaBF4 (96.95 mg, 0.880 mmol, CAS RN 13755-29-8), NiCl ₂ glyme (38.8 mg, 0.180 mmol, CAS RN 29046-78-4) and Mn powder (194.06 mg, 3.53 mmol) in MeOH (10 mL) were added 4-ethylpyridine (94.62 mg, 0.880 mmol, CAS RN 536-75-4 ). The mixture was stirred at 60 °C under N2 atmosphere for 16 h. The mixture was filtered and the filtrate was concentrated, and the residue was purified by reverse phase flash chromatography (FA) to obtain the desired product (60 mg, 10.2%) as a pale yellow foam. MS (ESI): m/z = 276.0 [MC ₄ H ₈ +H] ⁺ .

酸 向(4aR,8aS)-6-[3-(4-溴苯基)氮雜環丁烷-1-羰基]-4,4a,5,7,8,8a-六氫吡啶并[4,3-b][1,4]噁嗪-3-酮(300.0 mg, 0.760 mmol，實例110)及PdCl₂ (dppf).CH₂ Cl₂ (53.34 mg, 0.080 mmol)之溶液添加乙酸鉀(224.04 mg, 2.28 mmol)及雙(頻哪醇)二硼(289.84 mg, 1.14 mmol, CAS RN 73183-34-3)，用氮吹掃反應且在90℃下攪拌12 h。用水稀釋反應並用EtOAc萃取三次，將合併之有機層用水及鹽水洗滌，經硫酸鈉乾燥並在真空中濃縮以獲得黃色殘餘物，利用反相層析(FA)純化該殘餘物，獲得呈淺黃色固體之期望產物(230 mg, 84.1%)。MS (ESI): m/z = 360.5 [M+H]⁺ 。BB38 [4-[1-[(4aR,8aS)-3 -oxo- 4,4a,5,7,8,8a -hexahydropyrido [4,3-b][1,4] oxazine -6- carbonyl ] azetidin- 3 -yl ] phenyl ]

Acid to (4aR,8aS)-6-[3-(4-bromophenyl)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4, 3-b][1,4]oxazin-3-one (300.0 mg, 0.760 mmol, Example 110) and PdCl ₂ (dppf). CH ₂ Cl ₂ (53.34 mg, 0.080 mmol) was added with potassium acetate (224.04 mg, 2.28 mmol) and bis(pinacol) diboron (289.84 mg, 1.14 mmol, CAS RN 73183-34-3), the reaction was purged with nitrogen and stirred at 90°C for 12 h. The reaction was diluted with water and extracted three times with EtOAc, the combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated in vacuo to obtain a yellow residue, which was purified by reverse phase chromatography (FA) to obtain a light yellow color Solid expected product (230 mg, 84.1%). MS (ESI): m/z = 360.5 [M+H] ⁺ .

BB39 3 -cyclopropyl- 5-((4- fluorophenyl )( hexahydropyridin- 4 -yl ) methyl )-1,2,4 -oxadiazole hydrochloride is similar to BB16, from 4-( (3-Cyclopropyl-1,2,4-oxadiazol-5-yl)(4-fluorophenyl)methyl)hexahydropyridine-1-carboxylic acid tert-butyl ester was obtained as a colorless foam Product (0.170 g; 84.7%). MS (ESI): m/z = 302.3 [M+H] ⁺ .

Intermediate: a) 4-((3- Cyclopropyl- 1,2,4 -oxadiazol- 5- yl )(4- fluorophenyl ) methyl ) hexahydropyridine- 1- carboxylic acid tert-butyl The ester is similar to the BB25 intermediate, obtained from 2-(1-(third butoxycarbonyl)hexahydropyridin-4-yl)-2-(4-fluorophenyl)acetic acid and N'-hydroxycyclopropanecarboxamidine Product as a colorless foam (0.240 g; 80.7%). MS (ESI): m/z = 346.2 [MC ₄ H ₈ +H] ⁺ . b) 2-(1-( third butoxycarbonyl ) hexahydropyridin- 4 -yl )-2-(4- fluorophenyl ) acetic acid to 2-(4-fluorophenyl)-2-(hexahydro Pyridine-4-yl)acetic acid hydrobromide (535 mg, 1.55 mmol) in 1 M NaOH (in H ₂ O) (3.09 mL, 3.09 mmol) was added dropwise with di-tert-butyl dicarbonate Ester (368 mg, 391 µL, 1.68 mmol) in DME (5 mL), and the mixture was stirred at room temperature for 3 h. DME was evaporated. The residue was dissolved in approximately 1.2 mL of 10% citric acid in water (pH approximately 4) and EtOAc, and the layers were separated. The aqueous layer was extracted once with EtOAc. The organic layer was dried over MgSO ₄ , filtered and evaporated to obtain the desired compound (0.520 g; 99.6%) as a light brown solid. MS (ESI): m/z = 336.3 [MH] ^- . c) 2-(4- fluorophenyl )-2-( hexahydropyridin- 4 -yl ) acetic acid hydrobromide salt 4-(cyano(4-fluorophenyl)methyl)hexahydropyridine-1- A solution of tert-butyl formate (555 mg, 1.74 mmol, CAS RN 1824014-64-3) in 48% HBr (in water) (8.27 g, 5.55 mL, 49.1 mmol) was stirred under reflux for 4.5 hours. The mixture was evaporated. The light brown solid was suspended in 2-propanol (2 mL), homogenized and filtered. The filter cake was washed three times with 2-propanol (1 mL each time). The mother liquor was completely evaporated and dried under high vacuum in the presence of P ₂ O ₅ for 2 hours, yielding the desired product as a light brown solid (0.535 g; 96.5%). MS (ESI): m/z = 238.2 [M-HBr+H] ⁺ .

BB40 3-(3-( trifluoromethoxy ) phenyl ) azetidine 4 -toluenesulfonate is similar to BB28, from 3-(3-(trifluoromethoxy)phenyl)azacyclo The third butyl butane-1-carboxylate (CAS RN 2222044-21-3) gave the product as a colorless solid. MS (ESI): 218.1 [M+H] ⁺ .

BB41 [4- (azetidin-3-yl) phenyl] - 4- pentafluoro -λ6- thioalkoxy toluenesulfonate similar BB28, from 3- (4- (pentafluoroethyl group -l6-) Phenyl)azetidine-1-carboxylic acid tert-butyl ester gives the product as a colorless solid. MS (ESI): 260.1 [M+H] ⁺ .

酸(CAS RN 871507-70-9)獲得呈無色油狀物之產物。MS (ESI): m/z = 304.1 [M-C₄ H₈ +H]⁺ 。 Intermediate: 3-(4-( pentafluoro- l6- thio ) phenyl ) azetidine- 1- carboxylic acid tert-butyl ester is similar to BB35 intermediate, from (4-(pentafluoro-l6- Thio)phenyl)

Acid (CAS RN 871507-70-9) gives the product as a colorless oil. MS (ESI): m/z = 304.1 [MC ₄ H ₈ +H] ⁺ .

BB42 2-( azetidin- 3 -yl )-5 -chloropyridine bis (4 -toluenesulfonate ) is similar to BB28, from 3-(5-chloropyridin-2-yl)azetidine- 3-Butyl 1-formate and twice the amount of p-TsOH gave the product as a colorless solid. MS (ESI): m/z = 169.1 [M+H] ⁺ .

酸及3-碘氮雜環丁烷-1-甲酸第三丁基酯獲得呈無色油狀物之產物(0.045 g; 11.2%)。MS (ESI): m/z = 213.1 [M-C₄ H₈ +H]⁺ 。 Intermediate: 3-(5 -chloropyridin -2- yl ) azetidine- 1- carboxylic acid tert-butyl ester Similar to BB37 intermediate, from (5-chloropyridin-2-yl)

Acid and tert-butyl 3-iodoazetidine-1-carboxylate gave the product as a colorless oil (0.045 g; 11.2%). MS (ESI): m/z = 213.1 [MC ₄ H ₈ +H] ⁺ .

BB43 3-(2- fluoro- 4-( trifluoromethoxy ) phenyl ) azetidine 4 -toluenesulfonate is similar to BB28, from 3-(2-fluoro-4-(trifluoromethoxy Group) phenyl) azetidine-1-carboxylic acid tert-butyl ester to obtain the product as a colorless solid. MS (ESI): m/z = 236.1 [M+H] ⁺ .

酸(CAS RN 503309-10-2)獲得呈無色油狀物之產物。MS (ESI): m/z = 280.1 [M-C₄ H₈ +H]⁺ 。 Intermediate: 3-(2- fluoro- 4-( trifluoromethoxy ) phenyl ) azetidine- 1- carboxylic acid tert-butyl ester is similar to BB35 intermediate, from (2-fluoro-4- (Trifluoromethoxy)phenyl)

Acid (CAS RN 503309-10-2) gives the product as a colorless oil. MS (ESI): m/z = 280.1 [MC ₄ H ₈ +H] ⁺ .

BB44 3- [4- (2,2,2-T-trifluoroethyl) phenyl] azetidine trifluoroacetate similar BB26 intermediate a, from 3- [4- (2,2,2 -Trifluoroethyl)phenyl]azetidine-1-carboxylic acid tert-butyl ester to obtain the product as a yellow oil. MS (ESI): m/z = 216.2 [M+H] ⁺ .

Intermediate: 3-[4-(2,2,2- Trifluoroethyl ) phenyl ] azetidine- 1- carboxylic acid tert-butyl ester is similar to BB37 intermediate a, from 1-bromo-4 -(2,2,2-trifluoroethyl)benzene (CAS RN 155820-88-5) gives the product as a yellow oil. MS (ESI): m/z = 260.0 [MC ₄ H ₈ +H] ⁺ .

BB45 3-[4-[1-( trifluoromethyl ) cyclopropyl ] phenyl ] azetidine trifluoroacetate is similar to BB26 intermediate a, from 3-[4-[1-(trifluoro Methyl)cyclopropyl]phenyl]azetidine-1-carboxylic acid tert-butyl ester gives the product as a yellow oil. MS (ESI): m/z = 242.1 [M+H] ⁺ .

Intermediate: 3-[4-[1-( Trifluoromethyl ) cyclopropyl ] phenyl ] azetidine- 1- carboxylic acid tert-butyl ester is similar to BB37 intermediate, from 1-bromo-4 -[1-(trifluoromethyl)cyclopropyl]benzene (CAS RN 1227160-18-0) gives the product as a yellow oil. MS (ESI): m/z = 286.0 [MC ₄ H ₈ +H] ⁺ .

BB46 3-(3- fluoro- 4-( trifluoromethoxy ) phenyl ) azetidine 4 -toluenesulfonate is similar to BB28 a, from 3-(3-fluoro-4-(trifluoromethyl Oxy)phenyl)azetidine-1-carboxylic acid tert-butyl ester gives the product as a colorless solid. MS (ESI): m/z = 236.1 [M+H] ⁺ .

Intermediate: 3-(3- fluoro- 4-( trifluoromethoxy ) phenyl ) azetidine- 1- carboxylic acid tert-butyl ester is similar to BB37 intermediate, from 4-bromo-2-fluoro -1-(trifluoromethoxy)benzene (CAS RN 105529-58-6) gives the product as a colorless oil. MS (ESI): m/z = 280.1 [MC ₄ H ₈ +H] ⁺ .

BB47 3-(3- methyl- 4-( trifluoromethoxy ) phenyl ) azetidine 4 -toluenesulfonate is similar to BB28 a, from 3-(3-methyl-4-(tri Fluoromethoxy)phenyl)azetidine-1-carboxylic acid tert-butyl ester gives the product as a colorless solid. MS (ESI): m/z = 232.1 [M+H] ⁺ .

Intermediate: 3-(3- methyl- 4-( trifluoromethoxy ) phenyl ) azetidine- 1- carboxylic acid tert-butyl ester is similar to BB37 intermediate, from 4-bromo-2- Methyl-1-(trifluoromethoxy)benzene (CAS RN 887268-26-0) gives the product as a colorless oil. MS (ESI): m/z = 276.2 [MC ₄ H ₈ +H] ⁺ .

BB48 3-(3,5 -difluoro- 4-( trifluoromethoxy ) phenyl ) azetidine 4 -toluenesulfonate is similar to BB28 a, from 3-(3,5-difluoro- 4-(Trifluoromethoxy)phenyl)azetidine-1-carboxylic acid tert-butyl ester gives the product as a colorless solid. MS (ESI): m/z = 254.1 [M+H] ⁺ .

Intermediate: 3-(3,5 -Difluoro- 4-( trifluoromethoxy ) phenyl ) azetidine- 1- carboxylic acid tert-butyl ester is similar to BB37 intermediate a, from 5-bromo -1,3-difluoro-2-(trifluoromethoxy)benzene (CAS RN 115467-07-7) gives the product as a colorless solid. MS (ESI): m/z = 298.1 [MC ₄ H ₈ +H] ⁺ .

BB49 3-(2- chloro- 4-( trifluoromethoxy ) phenyl ) azetidine 4 -toluenesulfonate is similar to BB28 a, from 3-(2-chloro-4-(trifluoromethyl Oxy)phenyl)azetidine-1-carboxylic acid tert-butyl ester gives the product as a colorless solid. MS (ESI): m/z = 252.1 [M+H] ⁺ .

Intermediate: 3-(2- chloro- 4-( trifluoromethoxy ) phenyl ) azetidine- 1- carboxylic acid tert-butyl ester is similar to BB37 intermediate a, from 1-bromo-2- Chloro-4-(trifluoromethoxy)benzene (CAS RN 892845-59-9) gave the product as a colorless oil. MS (ESI): m/z = 296.1 [MC ₄ H ₈ +H] ⁺ .

BB50 3-(4-( bicyclo [1.1.1] pent- 1 -yl ) phenyl ) azetidine 4 -toluenesulfonate is similar to BB28 a, from 3-(4-(bicyclo[1.1 .1] Pent-1-yl)phenyl)azetidine-1-carboxylic acid tert-butyl ester to obtain the product as a colorless solid. MS (ESI): m/z = 200.2 [M+H] ⁺ .

Intermediate: 3-(4-( Bicyclo [1.1.1] pent- 1 -yl ) phenyl ) azetidine- 1- carboxylic acid tert-butyl ester is similar to BB37 intermediate a, from 1-( 4-bromophenyl)bicyclo[1.1.1]pentane (CAS RN 1823935-76-7) gives the product as a colorless oil. MS (ESI): m/z = 244.2 [MC ₄ H ₈ +H] ⁺ .

BB51 5-( azetidin- 3 -yl )-2-( trifluoromethoxy ) benzonitrile 4 -toluenesulfonate is similar to BB28, from 3-(3-cyano-4-(trifluoro Methoxy)phenyl)azetidine-1-carboxylic acid tert-butyl ester gave the product as a light brown gum. MS (ESI): m/z = 243.1 [M+H] ⁺ . This compound was used in the next step without further purification.

Intermediate: 3-(3- cyano- 4-( trifluoromethoxy ) phenyl ) azetidine- 1- carboxylic acid tert-butyl ester is similar to BB37 intermediate a, from 5-bromo-2 -(Trifluoromethoxy)benzonitrile (CAS RN 1210906-15-2) gives the product as a pale yellow oil. MS (ESI): m/z = 287.1 [MC ₄ H ₈ +H] ⁺ .

BB52 (1-(4-( azetidin- 3 -yl ) phenyl ) cyclopropyl ) methanol hydrochloride to 3-(4-(1-(hydroxymethyl)cyclopropyl)phenyl)nitrogen A solution of tert-butyl heterocyclobutane-1-carboxylate (40 mg, 132 µmol) in DCM (0.7 mL) was added 4 M HCl (330 µL, 1.32 mmol) in dioxane, and the mixture Stir at room temperature for 3 hours. Diethyl ether (2 mL) was added to the light yellow suspension, and the oily mixture was evaporated to obtain the desired compound as a light yellow oil. MS (ESI): m/z = 204.2 [M+H] ⁺ . This compound was used in the next step without further purification.

Intermediate : a) 3-(4-(1-( hydroxymethyl ) cyclopropyl ) phenyl ) azetidine- 1- carboxylic acid tertiary butyl ester 3-(4-(1-(methyl Oxycarbonyl) cyclopropyl) phenyl) azetidine-1-carboxylic acid tert-butyl ester (238 mg, 718 µmol) in THF (2 mL) ice-cold solution was added dropwise in THF 1 M LAH solution (718 µL, 718 µmol). The solution was stirred at 0°C for 1.25 hours, and then poured onto half-saturated aqueous NH ₄ Cl and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layer was dried over MgSO ₄ , filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography using a MPLC system on a 4 g column using a gradient of n-heptane: EtOAc (100:0 to 50:50) to provide the desired compound (0.151) as a colorless oil g; 69.3%). MS (ESI): m/z = 248.2 [MC ₄ H ₈ +H] ⁺ . b) 3-(4-(1-( methoxycarbonyl ) cyclopropyl ) phenyl ) azetidine- 1- carboxylic acid tert-butyl ester is similar to method A7, from 1-(4-bromobenzene Cyclopropane-1-carboxylic acid methyl ester (CAS RN 638220-35-6) and 3-bromoazetidine-1-carboxylic acid tert-butyl ester (CAS RN 1064194-10-0) obtained as colorless Solid product. MS (ESI): m/z = 276.2 [MC ₄ H ₈ +H] ⁺ .

BB53 4-( azetidin- 3 -yl )-1 -methyl -1H -indazole hydrochloride is similar to BB52 a, from 3-(1-methyl-1H-indazol-4-yl) nitrogen The third butyl heterocyclobutane-1-carboxylate gave the product as a light yellow solid. MS (ESI): m/z = 188.2 [M+H] ⁺ .

Intermediate : a) 3-(1 -methyl -1H- indazol- 4 -yl ) azetidine- 1- carboxylic acid tert-butyl ester similar to method A7, from 4-bromo-1-methyl -1H-indazole (CAS RN 365427-30-1) and tert-butyl 3-bromoazetidine-1-carboxylate (CAS RN 1064194-10-0) gave the product as a light brown oil . MS (ESI): m/z = 232.1 [MC ₄ H ₈ +H] ⁺ .

BB54 3-[4-( trifluoromethoxy ) phenyl ] pyrrolidinium trifluoroacetate is similar to BB26 intermediate a, from 3-[4-(trifluoromethoxy)phenyl]pyrrolidin-1- The third butyl formate gave the product as a light brown solid. MS (ESI): m/z = 232.6 [M+H] ⁺ .

酸(973.57 mg, 4.73 mmol, CAS RN 139301-27-2)、Na2CO3 (668.1 mg, 6.3 mmol)於1,4-二噁烷(20 mL)及水(5 mL)中之溶液添加[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II) (461.24 mg, 0.630 mmol)，且將混合物在100℃下在N₂ 氣氛下攪拌12 h。將反應濃縮且藉由矽膠層析(PE:EtOAc=20:1)進行純化，獲得呈淺黃色油狀物之期望產物(320 mg, 30.8%)。MS (ESI): m/z = 274.5 [M- C₄ H₈ +H]⁺ 。 Intermediate : a) 3-[4-( trifluoromethoxy ) phenyl ] pyrrolidine- 1- carboxylic acid tert-butyl ester is similar to BB17 intermediate a, from 3-[4-(trifluoromethoxy )Phenyl]-2,5-dihydropyrrole-1-carboxylic acid tert-butyl ester to give the product as a pale yellow oil (200 mg, 66.3%). MS (ESI): m/z = 276.5 [M- C ₄ H ₈ +H] ⁺ . b) 3-[4-( Trifluoromethoxy ) phenyl ]-2,5- dihydropyrrole- 1- carboxylic acid tert-butyl ester to 3-(((trifluoromethyl)sulfonyl)oxy Yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (1 g, 3.15 mmol, CAS RN 630121-86-7) and 4-(trifluoromethoxy)phenyl

A solution of acid (973.57 mg, 4.73 mmol, CAS RN 139301-27-2), Na2CO3 (668.1 mg, 6.3 mmol) in 1,4-dioxane (20 mL) and water (5 mL) was added (1, 1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (461.24 mg, 0.630 mmol), and the mixture was stirred at 100° C. under N ₂ atmosphere for 12 h. The reaction was concentrated and purified by silica gel chromatography (PE:EtOAc=20:1) to obtain the desired product (320 mg, 30.8%) as a pale yellow oil. MS (ESI): m/z = 274.5 [M- C ₄ H ₈ +H] ⁺ .

BB55 tributyl- (3- chloro -2- pyridyl ) stannane at -78 °C under N2 to 2-bromo-3-chloropyridine (576.0 mg, 2.99 mmol, CAS RN 96424-68-9) at The solution in toluene (20 mL) was added dropwise to 2.5 M n-BuLi (1.32 mL, 3.29 mmol) in hexane. The reaction mixture was stirred for 2 h, after which tributyltin chloride (1071.73 mg, 3.29 mmol, CAS RN 1461-22-9) was added. The reaction mixture was stirred at -78 °C for 2 h, warmed to room temperature and stirred for another 12 h, and then quenched with saturated NH 4 Cl solution (50 mL). The mixture was extracted with EtOAc (30 mL, three times), and the combined organic layer was washed with brine (15 mL), dried (Na ₂ SO ₄ ) and filtered. The filtrate was concentrated in vacuo to the desired product (1.1 g, 91.3%) as a pale yellow oil. MS (ESI): m/z = 404.1 [M+H] ⁺ .

BB56 6-( azetidin- 3 -yl )-1 -methyl -1H -indazole hydrochloride is similar to BB52 a, from 3-(1-methyl-1H-indazol-6-yl) nitrogen The third butyl heterocyclobutane-1-carboxylate gives the product as a colorless solid. MS (ESI): m/z = 188.1 [M+H] ⁺ .

Intermediate : a) 3-(1 -methyl -1H- indazol- 6- yl ) azetidine- 1- carboxylic acid tert-butyl ester similar to method A7, from 6-bromo-1-methyl -1H-indazole (CAS RN 365427-30-1) and 3-bromoazetidine-1-carboxylic acid tert-butyl ester (CAS RN 1064194-10-0) gave the product as a pale yellow oil . MS (ESI): m/z = 288.2 [M+H] ⁺ .

BB57 (4aR,8aS)-6-[3-[3-( trifluoromethoxy ) phenyl ] pyrrolidin- 1- carbonyl ]-4,4a,5,7,8,8a -hexahydropyrido [ 4,3-b][1,4] oxazin- 3 -one This product is similar to method A4, using 3-[3-(trifluoromethoxy)phenyl]pyrrolidine 2,2,2-tri Fluoroacetate is obtained as the desired product as a light yellow solid. MS (ESI): m/z = 414.3 [M+H] ⁺ .

酸(CAS RN 179113-90-7)以得到呈淺棕色油狀物之期望產物來獲得。MS (ESI): m/z = 274.5 [M-C₄ H₈ +H]⁺ 。 Intermediate : a) 3-[3-( trifluoromethoxy ) phenyl ] pyrrolidinium trifluoroacetate is similar to BB26 intermediate a, from 3-[3-(trifluoromethoxy)phenyl]pyrrole The third butyl pyridine-1-carboxylate gave the product as a light brown oil. MS (ESI): m/z = 232.6 [M+H] ⁺ . b) 3-[3-( Trifluoromethoxy ) phenyl ] pyrrolidine- 1- carboxylic acid tert-butyl ester This product is similar to BB54 intermediate a, from 3-[3-(trifluoromethoxy ) Phenyl]-2,5-dihydropyrrole-1-carboxylic acid tert-butyl ester to obtain the desired product as a pale yellow oil. MS (ESI): m/z = 276.5 [MC ₄ H ₈ +H] ⁺ . c) 3-[3-( Trifluoromethoxy ) phenyl ]-2,5- dihydropyrrole- 1- carboxylic acid tert-butyl ester This product is similar to BB54 intermediate b, from 3-(trifluoro Methoxy)phenyl

Acid (CAS RN 179113-90-7) was obtained as the desired product as a light brown oil. MS (ESI): m/z = 274.5 [MC ₄ H ₈ +H] ⁺ .

BB58 2- methyl- 3-(4-( trifluoromethoxy ) phenyl ) azetidine 2,2,2- trifluoroacetate similar to BB26 intermediate a, from 2-methyl-3 -(4-(trifluoromethoxy)phenyl)azetidine-1-carboxylic acid tert-butyl ester affords the product as a crude product. MS (ESI): m/z = 232.2 [M+H] ⁺ .

酸(222 mg, 1.08 mmol, CAS RN 139301-27-2)於二噁烷(2.87 mL)中之溶液。向該溶液添加碳酸銫(351 mg，1.08 mmol)。利用氬使RM脫氣，將小瓶密封且在攪拌的同時加熱至110℃持續18 h。使RM冷卻至室溫，之後利用2 mL飽和NaHCO₃ 水溶液淬滅並用DCM萃取三次。使合併之有機層經MgSO₄ 乾燥並在真空中濃縮，產生呈黃色油狀物之期望產物(71.1 mg; 29.9%)。MS (ESI): m/z = 276.2 [M-C₄ H₈ +H]⁺ 。b) (Z)-3-(2-((4- 甲氧基苯基 ) 磺醯基 ) 亞肼基 )-2- 甲基氮雜環丁烷 -1- 甲酸第三丁基酯 將4-甲氧基苯磺醯肼(180 mg, 890 µmol, CAS RN1950-68-1)及2-甲基-3-側氧基氮雜環丁烷-1-甲酸第三丁基酯(165 mg, 890 µmol, CAS RN 1408076-36-7)於DMSO d6 (593 µL)中之溶液加熱至60℃同時攪拌1 h。將反應混合物冷卻至室溫且傾倒於攪拌中之H₂ O上，釋放白色沈澱物。將該沈澱物過濾且再溶解於MeOH中。將溶劑在真空中去除，產生呈黃色油狀物之期望產物(265.5 mg；80.7%)。MS (ESI): m/z = 368.3 [M-H]^- 。 Intermediate : a) 2- Methyl- 3-(4-( trifluoromethoxy ) phenyl ) azetidine- 1- carboxylic acid tert-butyl ester is charged into the microwave tube (Z)-3- (2-((4-methoxyphenyl)sulfonyl)hydrazono)-2-methylazetidine-1-carboxylic acid tert-butyl ester (265.5 mg, 719 µmol) and (4 -(Trifluoromethoxy)phenyl)

A solution of acid (222 mg, 1.08 mmol, CAS RN 139301-27-2) in dioxane (2.87 mL). To this solution was added cesium carbonate (351 mg, 1.08 mmol). The RM was degassed with argon, the vial was sealed and heated to 110°C for 18 h while stirring. The RM was allowed to cool to room temperature, after which it was quenched with 2 mL of saturated aqueous NaHCO ₃ and extracted three times with DCM. The combined organic layer was dried over MgSO ₄ and concentrated in vacuo to give the desired product (71.1 mg; 29.9%) as a yellow oil. MS (ESI): m/z = 276.2 [MC ₄ H ₈ +H] ⁺ . b) (Z)-3-(2-((4 -methoxyphenyl ) sulfonyl ) hydrazono )-2 -methylazetidine- 1- carboxylic acid tert-butyl ester 4 -Methoxybenzenesulfonylhydrazine (180 mg, 890 µmol, CAS RN1950-68-1) and tert-butyl 2-methyl-3-oxo-azetidine-1-carboxylate (165 mg , 890 µmol, CAS RN 1408076-36-7) in DMSO d6 (593 µL) was heated to 60°C while stirring for 1 h. The reaction mixture was cooled to room temperature and poured onto stirring H ₂ O, releasing a white precipitate. The precipitate was filtered and redissolved in MeOH. The solvent was removed in vacuo to give the desired product (265.5 mg; 80.7%) as a yellow oil. MS (ESI): m/z = 368.3 [MH] ^- .

BB59 3-(3,3 -dimethyl -2,3 -dihydrobenzofuran -6- yl ) azetidine 4 -toluenesulfonate is similar to BB28, from 3-(3,3-di Methyl-2,3-dihydrobenzofuran-6-yl)azetidine-1-carboxylic acid tert-butyl ester gave the product as a colorless solid. MS (ESI): m/z = 204.2 [M+H] ⁺ .

Intermediate: 3-(3,3 -Dimethyl -2,3 -dihydrobenzofuran -6- yl ) azetidine- 1- carboxylic acid tert-butyl ester similar to method A7, from 6- Bromo-3,3-dimethyl-2,3-dihydrobenzofuran (CAS RN 140896-85-1) gives the product as a colorless solid. MS (ESI): m/z = 248.2 [MC ₄ H ₈ +H] ⁺ .

BB60 3-(3- chloro -5-(2,2,2- trifluoroethoxy ) phenyl ) pyrrolidine 4 -toluenesulfonate is similar to BB28, from 3-(3-chloro-5-(2 , 2,2-trifluoroethoxy)phenyl)pyrrolidine-1-carboxylic acid tert-butyl ester to give the product as a colorless oil. MS (ESI): m/z = 280.1 [M+H] ⁺ .

Intermediate : a) 3-(3- chloro -5-(2,2,2- trifluoroethoxy ) phenyl ) pyrrolidine- 1- carboxylic acid tert-butyl ester similar to method A7, from 1-bromo -3-chloro-5-(2,2,2-trifluoroethoxy)benzene gave the product as a colorless oil. MS (ESI): m/z = 324.1 [MC ₄ H ₈ +H] ⁺ . b) 1- Bromo- 3 -chloro -5-(2,2,2- trifluoroethoxy ) benzene 3-bromo-5-chlorophenol (330 mg, 1.59 mmol, CAS RN 56962-04-0) And a solution of 2,2,2-trifluoroethyl trifluoromethanesulfonate (554 mg, 2.39 mmol) in DMF (3 mL), potassium carbonate (440 mg, 3.18 mmol) was added, and the mixture was added over the weekend Stir at 50°C. After cooling, the reaction mixture was poured onto water and EtOAc, and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layer was washed twice with water, dried over MgSO ₄ , filtered and evaporated to provide the desired compound (0.484 g; 100%) as a colorless oil. This compound was used in the next step without further purification.

BB61 2-(4-( azetidin- 3 -yl ) phenyl )-2- methylpropanoic acid methyl ester 4 -toluenesulfonate similar to BB28, from 3-(4-(1-methoxy 3-Butyl-2-methyl-1-oxopropan-2-yl)phenyl)azetidine-1-carboxylic acid tert-butyl ester gives the product as a colorless gum. MS (ESI): m/z = 234.2 [M+H] ⁺ .

Intermediate: 3-(3,3 -Dimethyl -2,3 -dihydrobenzofuran -6- yl ) azetidine- 1- carboxylic acid tert-butyl ester similar to Method A7, from 2- (4-Bromophenyl)-2-methylpropionic acid methyl ester (CAS RN 154825-97-5) gave the product as a pale yellow oil. MS (ESI): m/z = 278.2 [MC ₄ H ₈ +H] ⁺ .

BB62 3-(3,5- dichlorophenyl ) pyrrolidine 4 -toluenesulfonate is similar to BB28, obtained from the third butyl 3-(3,5-dichlorophenyl)pyrrolidine-1-carboxylate The product is a brown oil. MS (ESI): m/z = 216.0 [M+H] ⁺ .

Intermediate: 3-(3,5- dichlorophenyl ) pyrrolidine- 1- carboxylic acid tert-butyl ester is similar to Method A7, from 1-bromo-3,5-dichlorobenzene (CAS RN 19752-55- 7) Obtain the product as a colorless oil. MS (ESI): m/z = 260.1 [MC ₄ H ₈ +H] ⁺ .

BB63 2-[4-( azetidin- 3 -yl ) phenyl ]-5-(2,2 -dimethylpropyl )-1,3,4 -oxadiazole 2,2,2- tri Fluoroacetate is similar to BB26 intermediate a, from 3-[4-[5-(2,2-dimethylpropyl)-1,3,4-oxadiazol-2-yl]phenyl]aza The third butyl cyclobutane-1-carboxylate gave the product as a light brown oil. MS (ESI): m/z = 272.6 [M+H] ⁺ .

Intermediate : a) 3-[4-[5-(2,2 -dimethylpropyl )-1,3,4 -oxadiazol- 2- yl ] phenyl ] azetidine- 1- The third butyl formate is similar to Method A7, obtained from 2-(4-bromophenyl)-5-(2,2-dimethylpropyl)-1,3,4-oxadiazole as a light brown oil Product. MS (ESI): m/z = 372.5 [M+H] ⁺ . b) 2-(4- Bromophenyl )-5-(2,2 -dimethylpropyl )-1,3,4 -oxadiazole toward 4-bromo-N'-(3,3-dimethyl To a solution of butylbutyroyl)benzohydrazide (5 g, 15.96 mmol) in toluene (102 mL) was added p-toluenesulfonic acid (5.5 g, 31.93 mmol), and then stirred at 110°C for 12 h. LCMS showed that the reaction was complete, the mixture was concentrated and the residue was purified by silica gel chromatography with PE: EtOAc = 10: 1 to elute the residue to give the desired product (1 g, 21.2%) as a light yellow solid. MS (ESI): m/z = 295.4 [M+H] ⁺ . c) 4- Bromo- N'-(3,3 -dimethylbutyranyl ) benzohydrazide to 4-bromobenzohydrazide (5.0 g, 23.25 mmol, CAS RN 5933-32-4) at 0°C And a solution of DIPEA (12.39 mL, 69.75 mmol) in DCM (50 mL) was added 3,3-dimethylbutyrochloride (3.76 g, 27.9 mmol, CAS RN 7065-46-5), and the mixture was at 20°C Stir for 12 h. The aqueous layer was extracted with EtOAc (200 mL, 3 times) and water (100 mL, 3 times). The separated organic layer was washed with water, dried over Na ₂ SO ₄ and evaporated to give the desired product (7 g, 96.1%) as a light yellow solid. MS (ESI): m/z = 315.4 [M+H] ⁺ .

BB64 3-(4-( T - butyl )-3 -methoxyphenyl ) azetidine 4 -toluenesulfonate is similar to BB28, from 3-(4-(T-butyl)-3 -Methoxyphenyl)azetidine-1-carboxylic acid tert-butyl ester to obtain the product as a crude product. MS (ESI): m/z = 220.2 [M+H] ⁺ .

Intermediate: 3-(4-( T-butyl )-3 -methoxyphenyl ) azetidine- 1- carboxylic acid tert-butyl ester is similar to Method A7, from 4-bromo-1-( Third butyl)-2-methoxybenzene (CAS RN 30788-02-4) to obtain the product as a light yellow oil. MS (ESI): m/z = 264.2 [MC ₄ H ₈ +H] ⁺ .

BB65 5-( azetidin- 3 -yl )-1 -methyl -1H -indazole 4 -toluenesulfonate is similar to BB28, from 3-(1-methyl-1H-indazol-5-yl ) Azetidine-1-carboxylic acid tert-butyl ester gives the product as a crude product. MS (ESI): m/z = 188.1 [M+H] ⁺ .

Intermediate: 3-(1 -methyl -1H- indazol- 5- yl ) azetidine- 1- carboxylic acid tert-butyl ester similar to method A7, from 5-bromo-1-methyl-1H -Indazole (CAS RN 465529-57-1 ) to obtain the product as a yellow oil. MS (ESI): m/z = 288.2 [M+H] ⁺ .

BB66 3-(4 -propylphenyl ) azetidine 4 -tosylate is similar to BB28, from 3-(4-propylphenyl)azetidine-1-carboxylic acid third butyl The ester gives the product as a crude product. MS (ESI): m/z = 176.1 [M+H] ⁺ .

Intermediate: 3-(4 -propylphenyl ) azetidine- 1- carboxylic acid tert-butyl ester similar to Method A7, from 1-bromo-4-propylbenzene (CAS RN 588-93-2 ) To obtain the product as a pale yellow oil. MS (ESI): m/z = 220.2 [MC ₄ H ₈ +H] ⁺ .

BB67 3-(4-( trifluoromethoxy )-3-( trifluoromethyl ) phenyl ) azetidine 4 -toluenesulfonate is similar to BB28, from 3-(4-(trifluoromethyl Oxy)-3-(trifluoromethyl)phenyl)azetidine-1-carboxylic acid tert-butyl ester to obtain the product as a crude product. MS (ESI): m/z = 286.1 [M+H] ⁺ .

Intermediate: 3-(4-( trifluoromethoxy )-3-( trifluoromethyl ) phenyl ) azetidine- 1- carboxylic acid tert-butyl ester similar to method A7, from 4-bromo -1-(trifluoromethoxy)-2-(trifluoromethyl)benzene (CAS RN 933674-89-6) gave the product as a light yellow oil. MS (ESI): m/z = 330.1 [MC ₄ H ₈ +H] ⁺ .

BB68 3-[4-[[1-( trifluoromethyl ) cyclopropyl ] methoxy ] phenyl ] azetidine 4-2,2,2- trifluoroacetate is similar to BB26 intermediate a , Obtained from 3-[4-[[1-(trifluoromethyl)cyclopropyl]methoxy]phenyl]azetidine-1-carboxylic acid tert-butyl ester as a yellow oil . MS (ESI): m/z = 272.1 [M+H] ⁺ .

Intermediate: 3-[4-[[1-( trifluoromethyl ) cyclopropyl ] methoxy ] phenyl ] azetidine- 1- carboxylic acid tert-butyl ester similar to method A7, since 1 -Bromo-4-[[1-(trifluoromethyl)cyclopropyl]methoxy]benzene (CAS RN 1594130-28-5) gives the product as a pale yellow oil. MS (ESI): m/z = 316.1 [MC ₄ H ₈ +H] ⁺ .

BB69 3-[4-(2,2,2- trifluoro -1,1 -dimethyl - ethyl ) phenyl ] azetidine 2,2,2- trifluoroacetate is similar to BB26 intermediate a, obtained from 3-[4-(2,2,2-trifluoro-1,1-dimethyl-ethyl)phenyl]azetidine-1-carboxylic acid tert-butyl ester as a yellow oil Product. MS (ESI): m/z = 244.1 [M+H] ⁺ .

Intermediate: 3-[4-(2,2,2- Trifluoro -1,1 -dimethyl - ethyl ) phenyl ] azetidine- 1- carboxylic acid tert-butyl ester similar to Method A7 , Obtained from 1-bromo-4-(2,2,2-trifluoro-1,1-dimethyl-ethyl)benzene (CAS RN 1225380-05-1) as a pale yellow oil. MS (ESI): m/z = 288.1 [MC ₄ H ₈ +H] ⁺ .

BB70 3-[4-( azetidin- 3 -yl ) phenyl ]-5-(2,2 -dimethylpropyl )-1,2,4 -oxadiazole 2,2,2- tri Fluoroacetate is similar to BB26 intermediate a, from 3-[4-[5-(2,2-dimethylpropyl)-1,2,4-oxadiazol-3-yl]phenyl]aza The third butyl cyclobutane-1-carboxylate gave the product as a pale yellow oil. MS (ESI): m/z = 272.6 [M+H] ⁺ .

Intermediate : a) 3-[4-[5-(2,2 -dimethylpropyl )-1,2,4 -oxadiazol- 3 -yl ] phenyl ] azetidine- 1- Tertiary butyl formate was added to 3-[4-(N-hydroxyformamidino)phenyl]azetidine-1-carboxylic acid tert-butyl ester (770.0 mg, 2.64 mmol) and DIPEA at 0°C. (1.41 mL, 7.93 mmol) in toluene (6 mL) was added 3,3-dimethylbutyrochloride (426.88 mg, 3.17 mmol, CAS RN 7065-46-5), and the mixture was stirred at 25°C 10 min, then raise the temperature to 80 °C and stir for 12 h. The mixture was evaporated and the residue was purified by silica gel chromatography (PE: EtOAc = 10: 1) to give the desired product (620 mg, 63.2%) as a light brown oil. MS (ESI): m/z = 316.5 [MC ₄ H ₈ +H] ⁺ . b) 3-[4-(N - Hydroxyformamidinyl ) phenyl ] azetidine- 1- carboxylic acid tert-butyl ester to hydroxylamine hydrochloride (349.71 mg, 5.03 mmol) in ethanol (8 mL) The solution in was added sodium carbonate (266.69 mg, 2.52 mmol) in water (2 mL) and stirred at 20°C for 25 min. Then 3-(4-cyanophenyl)azetidine-1-carboxylic acid tert-butyl ester (1000.0 mg, 3.87 mmol, CAS RN 206446-41-5) was added, and the mixture was stirred at 95°C for 12 h. The mixture was diluted with water, concentrated under vacuum to remove EtOH, the residue was partitioned between EtOAc (100 mL) and water (100 mL × 3), then saturated sodium chloride (50 mL), dried over sodium sulfate and evaporated To give the desired product (773 mg, 68.5%) as a light yellow oil. MS (ESI): m/z = 292.5 [M+H] ⁺ .

BB71 (4aR,8aS)-6-[3-[4-(2,2,2- trifluoro- 1 -methyl - ethoxy ) phenyl ] azetidine- 1- carbonyl ]-4, 4a,5,7,8,8a -hexahydropyrido [4,3-b][1,4] oxazin- 3 -one is similar to method A4, from 3-[4-(2,2,2- Trifluoro-1-methyl-ethoxy)phenyl]azetidine 2,2,2-trifluoroacetate to obtain the product as a pale yellow solid. MS (ESI): m/z = 428.3 [M+H] ⁺ .

Intermediate: a) 3-[4-(2,2,2- trifluoro- 1 -methyl - ethoxy ) phenyl ] azetidine 2,2,2- trifluoroacetate similar to BB26 Intermediate a, obtained from 3-[4-(2,2,2-trifluoro-1-methyl-ethoxy)phenyl]azetidine-1-carboxylic acid tert-butyl ester as pale yellow The product of oil. MS (ESI): m/z = 246.1 [M+H] ⁺ . b) 3-[4-(2,2,2- Trifluoro- 1 -methyl - ethoxy ) phenyl ] azetidine- 1- carboxylic acid tert-butyl ester is similar to Method A7, from 1 -Bromo-4-(2,2,2-trifluoro-1-methyl-ethoxy)benzene (CAS RN 1239611-43-8) gives the product as a colorless solid. MS (ESI): m/z = 290.1 [MC ₄ H ₈ +H] ⁺ .

BB72 3-(3 -methoxy- 4 -methylphenyl ) azetidine 4 -toluenesulfonate similar to BB28, from 3-(3-methoxy-4-methylphenyl) nitrogen The third butyl heterocyclobutane-1-carboxylate gives the product as a colorless solid. MS (ESI): m/z = 178.1 [M+H] ⁺ .

Intermediate: 3-(3 -methoxy- 4 -methylphenyl ) azetidine- 1- carboxylic acid tert-butyl ester similar to method A7, from 4-bromo-2-methoxy-1 -Toluene (CAS RN 67868-73-9) gives the product as a light brown oil. MS (ESI): m/z = 222.1 [MC ₄ H ₈ +H] ⁺ .

BB73 4-((4- fluorophenyl )((1 -methyl -5-( trifluoromethyl )-1H- pyrazol- 3 -yl ) oxy ) methyl ) hexahydropyridine hydrochloride is similar BB16, from 4-((4-fluorophenyl)((1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)oxy)methyl)hexahydropyridine-1- The third butyl formate gave the product as a colorless foam (0.194 g; 98.0%). MS (ESI): m/z = 358.2 [M+H] ⁺ .

Intermediate: 4-((4- fluorophenyl )((1 -methyl -5-( trifluoromethyl )-1H- pyrazol- 3 -yl ) oxy ) methyl ) hexahydropyridine- 1- A yellow solution of tert-butyl formate to tri-n-butylphosphine (327 mg, 399 µL, 1.62 mmol) and azodimethidine (408 mg, 1.62 mmol) in toluene (12.5 mL) Add 3-((4-fluorophenyl)(hydroxy)methyl)hexahydropyridine-1-carboxylic acid tert-butyl ester (250 mg, 808 µmol, CAS RN 160296-41-3), and place the mixture in the room Stir at temperature for 20 min. This produced a light yellow solution. 1-Methyl-5-(trifluoromethyl)-1H-pyrazol-3-ol (268 mg, 1.62 mmol, CAS RN 119022-51-4) was added to obtain a suspension. After stirring at room temperature for 75 min., heating was performed. After stirring at 65°C for 19 h, the reaction mixture was cooled to room temperature. Silicone was added and the mixture was evaporated. The compound was purified by silica gel chromatography using a MPLC (ISCO) system on a 12 g column using n-heptane: EtOAc gradient (100:0 to 50:50) to obtain a colorless gum. Compound (0.230 g; 62.2%). MS (ESI): m/z = 358.2 [M-Boc+H] ⁺ .

BB74 3-[1-[4- Trifluoromethyl ) phenyl ] ethoxy ] azetidine to 3-(1-(4-(trifluoromethyl)phenyl)ethoxy)aza A solution of tert-butyl cyclobutane-1-carboxylate (0.04 g, 0.116 mmol) in DCM (0.6 mL) was added TFA (0.178 mL, 2.32 mmol), and the reaction mixture was stirred at room temperature for 30 min. The solvent was removed under reduced pressure, and the residue was dissolved in EtOAc, poured into saturated aqueous Na ₂ CO ₃ (5 mL), and the aqueous layer was extracted twice with EtOAc (10 mL each time). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude title compound (0.025 g, 88%) as a colorless gum; MS (ESI): m/z = 246.2 [M+H] ⁺ .

Intermediate: 3-[1-[4-( Trifluoromethyl ) phenyl ] ethoxy ] azetidine- 1- carboxylic acid tert-butyl ester 3-hydroxyl group cooled to 0°C using an ice bath A solution of azetidine-1-carboxylic acid tert-butyl ester (0.1 g, 0.577 mmol) in DMF (5 mL) was added NaH (60% in mineral oil; 0.023 g, 0.577 mmol), and the reaction The mixture was stirred at this temperature for 15 min. Then, 1-(1-bromoethyl)-4-(trifluoromethyl)benzene (0.161 g, 0.635 mmol, CAS RN 68120-42-3) was added, and the mixture was warmed to room temperature and stirring was continued overnight. The mixture was poured into saturated aqueous ammonium chloride solution (15 mL) and extracted twice with EtOAc (20 mL each time). The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel flash chromatography using an EtOAc gradient (0% to 70%) in n-heptane to obtain the title compound (0.045 g, 22.6%) as a colorless amorphous solid. MS (ESI): m/z = 290.2 [MC ₄ H ₈ +H] ⁺ .

BB75 4-[1-[4-( trifluoromethyl ) phenyl ] ethoxy ] hexahydropyridine hydrochloride is similar to BH1, using 4-hydroxyhexahydropyridine-1-carboxylic acid in the intermediate step third Butyl ester (CAS RN 109384-19-2), and then use 4 M HCl/dioxane in MeOH instead of TFA/DCM for the deprotection step to obtain the product. Colorless solid; MS (ESI): 274.1 [M+H] ⁺ .

BB76 5- (azetidin-3-yl) -2-methoxy - pyridin-4- toluenesulfonate similar BB28, using 3- (6-methoxy-3-yl) azetidin Alkane-1-carboxylic acid tert-butyl ester to obtain the product. Colorless solid. MS (ESI) = 165.1 [M+H] ⁺ .

酸(CAS RN 163105-89-3)獲得呈無色油狀物之產物。MS (ESI) = 265.2 [M+H]⁺ 。 Intermediate: 3-(6 -methoxypyridin- 3 -yl ) azetidine- 1- carboxylic acid tert-butyl ester Similar to BB35 intermediate, using (6-methoxypyridin-3-yl)

Acid (CAS RN 163105-89-3) gives the product as a colorless oil. MS (ESI) = 265.2 [M+H] ⁺ .

BB77 3-[3- chloro- 4-( trifluoromethoxy ) phenyl ] azetidine 4 -toluenesulfonate is similar to BB28, using 3-[3-chloro-4-(trifluoromethoxy Radical) phenyl] azetidine-1-carboxylic acid tert-butyl ester to obtain the product as a colorless solid; MS (ESI) = 252.1 [M+H] ⁺ .

酸(CAS RN 870822-79-0)獲得呈無色液體之產物。MS (ESI) = 296.1 [M-C₄ H₈ +H]⁺ 。 Intermediate: 3-[3- chloro- 4-( trifluoromethoxy ) phenyl ] azetidine- 1- carboxylic acid tert-butyl ester is similar to the BB35 intermediate, using (3-chloro-4- (Trifluoromethoxy)phenyl)

Acid (CAS RN 870822-79-0) gives the product as a colorless liquid. MS (ESI) = 296.1 [MC ₄ H ₈ +H] ⁺ .

BB78 (4aR,8aS)-6-[3-[3- bromo- 4-( trifluoromethoxy ) phenyl ] azetidine- 1- carbonyl ]-4,4a,5,7,8, 8a -hexahydropyrido [4,3-b][1,4] oxazin- 3 -one is similar to Example 132, using 3-[3-bromo-4-(trifluoromethoxy)phenyl]nitrogen Heterocyclobutane 4-tosylate gave the product as a pale yellow solid. MS (ESI) = 480.1 [M+H] ⁺ .

酸(MFCD22580724; Apollo Scientific)獲得呈無色黏性油狀物之產物。MS (ESI) = 342.0 [M-C₄ H₈ +H]⁺ 。 Intermediate: a) 3-[3- Bromo- 4-( trifluoromethoxy ) phenyl ] azetidine 4 -toluenesulfonate is similar to BB28, using 3-[3-bromo-4-( Trifluoromethoxy)phenyl]azetidine-1-carboxylic acid tert-butyl ester gives the product as a colorless solid. MS (ESI) = 296.0 [M+H] ⁺ . b) 3-[3- Bromo- 4-( trifluoromethoxy ) phenyl ] azetidine- 1- carboxylic acid tert-butyl ester is similar to the BB35 intermediate, using (3-bromo-4-( Trifluoromethoxy)phenyl)

Acid (MFCD22580724; Apollo Scientific) gave the product as a colorless viscous oil. MS (ESI) = 342.0 [MC ₄ H ₈ +H] ⁺ .

BB79 3-[3- fluoro- 4-( trifluoromethyl ) phenyl ] azetidine 4 -toluenesulfonate is similar to BB28, using 3-[3-fluoro-4-(trifluoromethyl) Phenyl]azetidine-1-carboxylic acid tert-butyl ester gives the product. Colorless solid. MS (ESI): 220.1 [M+H] ⁺ .

Intermediate: 3-[3- fluoro- 4-( trifluoromethyl ) phenyl ] azetidine- 1- carboxylic acid tert-butyl ester is similar to the BB37 intermediate, using 4-bromo-2-fluoro- 1-(Trifluoromethyl)benzene gives the product as a colorless viscous oil. MS (ESI) = 264.1 [MC ₄ H ₈ +H] ⁺ .

BB80 (4aR,8aS)-6-[4-[(3,4 -dimethoxyphenyl )-(2- pyridyl ) methyl ] hexahydropyridine- 1- carbonyl ]-4,4a,5, 7,8,8a -hexahydropyrido [4,3-b][1,4] oxazin- 3 -one will 2-[(3,4-dimethoxyphenyl)-(4-hexahydro Pyridyl)methyl)pyridine (101 mg, 0.320 mmol), cesium carbonate (97 mg, 0.30 mmol) and (4aR,8aS)-3-pentoxy-4,4a,5,7,8,8a-hexa Hydropyrido[4,3-b][1,4]oxazine-6-carboxylic acid (4-nitrophenyl) ester (intermediate BB15a) (80 mg, 0.25 mmol) in DMF (5 mL) The solution was stirred at 25°C for 16 h. The solution was poured into brine (10 mL) and extracted twice with EtOAc (10 mL each time). The combined organic layer was concentrated under vacuum to obtain a residue, which was purified by preparative HPLC (TFA condition) to obtain (4aR, 8aS)-6-[4-[(3,4- Dimethoxyphenyl)-(2-pyridyl)methyl]hexahydropyridin-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][ 1,4] Oxazin-3-one (60 mg, 49%). MS (ESI): m/z = 495.3 [M+H] ⁺ .

Intermediate : a) 4-(3,4 -Dimethoxybenzyl ) hexahydropyridine- 1- carboxylic acid tert-butyl ester at -78°C to 4-bromoveratrole (12.4 g, 57.3 A solution of mmol) in THF (200 mL) was added butyllithium solution (28.6 mL, 71.6 mmol), and the solution was stirred at -78°C for 1 h. Then, at -78°C, 4-[methoxy(methyl)aminecarboxamide]hexahydropyridine-1-carboxylic acid tert-butyl ester (CAS No. 139290-70-3) (13.0 g, 47.7 mmol) was added And continue to stir at -78 °C for 5 h. The solution was poured into brine (20 mL) and extracted with EtOAc (2×10 mL). The combined organic layer was concentrated under vacuum to obtain a residue, which was purified by flash column chromatography (PE: EtOAc = 2: 1) to give the title compound as a white solid. MS (ESI): m/z = 372.1 [M+Na] ⁺ . b) 4-[C-(3,4 -dimethoxyphenyl )-N-( p-tolylsulfonylamino ) iminecarbonyl ] hexahydropyridine- 1- carboxylic acid tert-butyl ester 4 -Toluenesulfonylhydrazine (6.40 g, 34.3 mmol) and 4-(3,4-dimethoxybenzyl)hexahydropyridine-1-carboxylic acid tert-butyl ester (10.0 g, 28.6 mmol) in 1 , 4-dioxane (200 mL) was stirred at 80 °C for 24 h. The reaction solution was concentrated under vacuum to obtain a residue, which was purified by flash column chromatography (petroleum ether: EtOAc = 2: 1) to obtain the title compound (8.0 g, 54%) as a pale yellow solid. MS (ESI): m/z = 540.2 [M+Na] ⁺ . c) 4-[(3,4 -Dimethoxyphenyl )-(2- pyridyl ) methylene ] hexahydropyridine- 1- carboxylic acid tert-butyl ester 2-bromopyridine (1.11 mL, 11.6 mmol), 4-[ C -(3,4-dimethoxyphenyl)- N -( p-tolylsulfonylamino )iminecarbonyl]hexahydropyridine-1-carboxylic acid tert-butyl ester ( 3.00 g, 5.8 mmol), lithium tert-butoxide (557 mg, 6.95 mmol) and bis(triphenylphosphine) palladium(II) chloride (407 mg, 0.580 mmol) in 1,4-dioxane (37 The mixture in mL) was stirred under N ₂ at 90 °C for 16 h. The solid was filtered off and the solution was poured into brine (30 mL), and then extracted with EtOAc (2×20 mL). The combined organic layer was concentrated under vacuum. The residue was purified by flash column chromatography (petroleum ether: EtOAc = 1:1) to obtain the desired compound (280 mg, 12%) as a colorless oil. MS (ESI): m/z = 411.3 [M+H] ⁺ . d) 2-[(3,4 -dimethoxyphenyl )-(4 -hexahydropyridinyl ) methyl ] pyridine will 4-[(3,4-dimethoxyphenyl)-(2 -Pyridyl)methylene]hexahydropyridine-1-carboxylic acid tert-butyl ester (280 mg, 0.680 mmol) and trifluoroacetic acid (0.53 mL, 6.82 mmol) in DCM (10 mL) at 25°C Stir for 4 h. The solution was concentrated under vacuum to give the title compound (200 mg, 94%) as a colorless oil. MS (ESI): m/z = 311.1 [M+H] ⁺ . e) 2-[(3,4 -dimethoxyphenyl )-(4- hexahydropyridyl ) methyl ] pyridine will 2-[(3,4-dimethoxyphenyl)-(4- A solution of hexahydropyridinyl)methyl)pyridine (200 mg, 0.640 mmol) and Pd/C (69 mg, 0.060 mmol) in DMF (5 mL) was stirred at 25°C under H ₂ (760 mmHg) 6 h. The solution was concentrated under vacuum to obtain a residue, which was purified by preparative HPLC (TFA condition) to obtain the compound (150 mg, 71%) as a colorless oil. MS (ESI): m/z = 313.3 [M+H] ⁺ .

BB81 d) (4aR,8aS)-6-[4-[(3,4 -dimethoxyphenyl )-(3- pyridyl ) methyl ] hexahydropyridine- 1- carbonyl ]-4,4a, 5,7,8,8a -hexahydropyrido [4,3-b][1,4] oxazin- 3 -one will 3-[(3,4-dimethoxyphenyl)-(4- Hexahydropyridyl)methyl)pyridine (126 mg, 0.400 mmol), cesium carbonate (122 mg, 0.370 mmol) and (4a R ,8a S )-3-oxo-4,4a,5,7,8 ,8a-hexahydropyrido[4,3- b ][1,4]oxazine-6-carboxylic acid (4-nitrophenyl) ester (intermediate BB15a) (100 mg, 0.310 mmol) in DMF (5 mL) was stirred at 25 °C for 16 h. The solution was poured into brine (10 mL) and extracted with EtOAc (2×10 mL). The combined organic layer was concentrated under vacuum to obtain a residue, which was purified by preparative HPLC (TFA condition) to obtain the desired compound (80 mg, 52%) as a white solid. MS (ESI): m/z = 495.3 [M+H] ⁺ .

Intermediate : a) 4-[(3,4 -Dimethoxyphenyl )-(3- pyridyl ) methylene ] hexahydropyridine- 1- carboxylic acid tert-butyl ester 4-[ C -( 3,4-dimethoxyphenyl) - N - (p-tolyl sulfonic acyl group) imide carbonyl] -piperidine-1-carboxylic acid tert-butyl ester (intermediate b, example 118/119) (2.00 g, 3.86 mmol), 3-bromopyridine (0.56 mL, 5.8 mmol), lithium tertiary butoxide (464 mg, 5.8 mmol) and bis(triphenylphosphine) palladium(II) chloride (271 mg, A mixture of 0.390 mmol) in DMF (30 mL) was stirred under N ₂ at 90 °C for 16 h. The mixture was filtered and the filtrate was poured into brine (50 mL), and then extracted with EtOAc (2×40 mL). The combined organic layer was concentrated under vacuum to obtain a residue, which was purified by flash column chromatography (petroleum ether: EtOAc = 2: 1). 3-[(3,4-Dimethoxyphenyl)-(3-pyridyl)methylene]hexahydropyridine-1-carboxylic acid tert-butyl ester (600 mg, 38) was obtained as a colorless oil %). MS (ESI): m/z = 411.2 [M+H] ⁺ . b) 3-[(3,4 -dimethoxyphenyl )-(4 -hexahydropyridinyl ) methyl ] pyridine trifluoroacetate will 4-[(3,4-dimethoxyphenyl )-(3-pyridyl)methylene]hexahydropyridine-1-carboxylic acid tert-butyl ester (600 mg, 1.46 mmol) and trifluoroacetic acid (1.13 mL, 15 mmol) in DCM (10 mL) The solution was stirred at 25°C for 4 h. The solution was concentrated under vacuum to give crude 3-[(3,4-dimethoxyphenyl)-(4-hexahydropyridinyl)methyl]pyridine (450 mg, 49) as a brown oil %, in the form of TFA salt), which was used directly in the next step. MS (ESI): m/z = 311.1 [M+H] ⁺ . c) 3-[(3,4 -dimethoxyphenyl )-(4- hexahydropyridyl ) methyl ] pyridine will 3-[(3,4-dimethoxyphenyl)-(4- A mixture of hexahydropyridinyl)methyl)pyridine (450 mg, 0.710 mmol) and Pd/C (38 mg, 0.040 mmol) in DMF (10 mL) was stirred under H ₂ (760 mmHg) at 25°C 16 h. The mixture was filtered and concentrated under vacuum to obtain a residue, which was purified by preparative HPLC (TFA conditions) to obtain the desired compound (220 mg, 99%) as a colorless oil. MS (ESI): m/z = 313.2 [M+H] ⁺ .

BB82 (4aR,8aS)-6-[4-[(3,4 -dimethoxyphenyl )-(4- pyridyl ) methyl ] hexahydropyridine- 1- carbonyl ]-4,4a,5, 7,8,8a -hexahydropyrido [4,3-b][1,4] oxazin- 3 -one will 4-[(3,4-dimethoxyphenyl)-(4-hexahydro Pyridyl)methyl)pyridine (100 mg, 0.320 mmol), cesium carbonate (97 mg, 0.30 mmol) and (4a R ,8a S )-3-pentoxy-4,4a,5,7,8,8a -Hexahydropyrido[4,3- b ][1,4]oxazine-6-carboxylic acid (4-nitrophenyl) ester (intermediate BB15a) (80 mg, 0.25 mmol) in DMF (4 mL) The medium solution was stirred at 25°C for 16 h. The solution was poured into brine (10 mL) and extracted twice with EtOAc (10 mL each time). The combined organic layer was concentrated under vacuum to obtain a residue, which was purified by preparative HPLC (TFA condition) to obtain the title compound (60 mg, 49%) as a white solid. MS (ESI): m/z = 495.3 [M+H] ⁺ .

Intermediate : a) 4-[(3,4 -Dimethoxyphenyl )-(4- pyridyl ) methylene ] hexahydropyridine- 1- carboxylic acid tert-butyl ester 4-bromopyridine (0.56 mL, 5.8 mmol), 4-[ C -(3,4-dimethoxyphenyl)- N -(p-tolylsulfonylamino)iminecarbonyl]hexahydropyridine-1-carboxylic acid third butyl Ester (Intermediate b, Example 118/119) (2.00 g, 3.86 mmol), lithium tertiary butoxide (464 mg, 5.8 mmol) and bis(triphenylphosphine) palladium(II) chloride (271 mg, A mixture of 0.390 mmol) in DMF (30 mL) was stirred under N ₂ at 90 °C for 16 h. The mixture was filtered and the filtrate was poured into brine (30 mL), and then extracted with EtOAc (2×20 mL). The combined organic layer was concentrated under vacuum to obtain a residue, which was purified by flash column chromatography (petroleum ether: EtOAc = 2:1). 3-[(3,4-Dimethoxyphenyl)-(4-pyridyl)methylene]hexahydropyridine-1-carboxylic acid tert-butyl ester (400 mg, 25) was obtained as a colorless oil %). MS (ESI): m/z = 411.3 [M+H] ⁺ . b) 4-[(3,4 -dimethoxyphenyl )-(4 -hexahydropyridinyl ) methyl ] pyridine will 4-[(3,4-dimethoxyphenyl)-(4 -Pyridyl)methylene]hexahydropyridine-1-carboxylic acid tert-butyl ester (400 mg, 0.970 mmol) and trifluoroacetic acid (0.75 mL, 9.7 mmol) in DCM (15 mL) at 25°C Stir for 4 h. The solution was concentrated under vacuum to give crude 4-[(3,4-dimethoxyphenyl)-(4-hexahydropyridinyl)methyl]pyridine (as TFA salt) as a brown oil ; 250 mg, 83%), which was used directly in the next step. MS (ESI): m/z = 311.2 [M+H] ⁺ . c) 4-[(3,4 -dimethoxyphenyl )-(4- hexahydropyridyl ) methyl ] pyridine will 4-[(3,4-dimethoxyphenyl)-(4- A mixture of hexahydropyridinyl)methyl)pyridine (250 mg, 0.810 mmol) and Pd/C (43 mg, 0.040 mmol) in DMF (6 mL) was stirred at 25°C under H ₂ (760 mmHg) 16 h. The mixture was filtered and concentrated under vacuum to obtain a residue, which was purified by preparative HPLC (TFA conditions) to obtain 4-[(3,4-dimethoxyphenyl)- as a colorless oil (4-Hexahydropyridyl)methyl]pyridine (200 mg, 79%). MS (ESI): m/z = 313.2 [M+H] ⁺ .

BB83 (4aR,8aS)-6-[4-[(3- methylsulfonylphenyl )-(3- pyridyl ) methyl ] hexahydropyridine- 1- carbonyl ]-4,4a,5,7 ,8,8a -hexahydropyrido [4,3-b][1,4] oxazin- 3 -one, 3-[(3-methylsulfonylphenyl)-(4-hexahydropyridyl )Methyl]pyridine (110 mg, 0.330 mmol) and (4a R ,8a S )-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3- b ] A solution of [1,4]oxazine-6-carboxylic acid (4-nitrophenyl) ester (intermediate BB15a) (160 mg, 0.500 mmol) in pyridine (5.5 mL) was stirred at 90°C for 16 h. The solution was concentrated under vacuum to obtain a residue, which was purified by preparative HPLC (TFA conditions) to give (4a R , 8a S )-6-[4-[(3-methyl Sulfonylphenyl)-(3-pyridyl)methyl]hexahydropyridin-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3- b ][1 , 4] Oxazin-3-one (95 mg, 61%). MS (ESI): m/z = 513.3 [M+H] ⁺ .

Intermediate: a) 4- [N- (p-tolyl sulfonic acyl group) -C- (3- pyridyl) imide carbonyl] -piperidine-1-carboxylic acid tert-butyl ester 4-toluenesulfonamide Hydrazine (1.54 g, 8.27 mmol) and tert-butyl 4-(pyridine-3-carbonyl)hexahydropyridine-1-carboxylate (CAS No. 148148-35-0) (2.00 g, 6.89 mmol) in 1, The solution in 4-dioxane (200 mL) was stirred at 80°C for 16 h. The reaction mixture was concentrated under vacuum to obtain a residue, which was purified by flash column chromatography (petroleum ether: EtOAc = 2:1) to give 4-[ N- (p-tolylsulfonate as a pale yellow solid acyl amino) - C - (3- pyridyl) imide carbonyl] -piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 63%), MS (ESI): m / z = 403.1 [MC ₄ H ₈ +H] ⁺ . b) 4-[(3 -Methylsulfonylphenyl )-(3- pyridyl ) methylene ] hexahydropyridine- 1- carboxylic acid tert-butyl ester 3-bromophenylmethylbenzene (1.54 g, 6.54 mmol), 4-[ N -(p-tolylsulfonylamino)- C -(3-pyridyl)iminocarbonyl]hexahydropyridine-1-carboxylic acid tert-butyl ester (2.00 g, 4.36 mmol), lithium tertiary butoxide (524 mg, 6.54 mmol) and bis(triphenylphosphine) palladium(II) chloride (918 mg, 1.31 mmol) in 1,4-dioxane (30 mL) The solution was stirred at 90°C for 16 h. The reaction was diluted with EtOAc (20 mL), and then filtered through celite. The filtrate was dried over Na ₂ SO ₄ , filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether: EtOAc = 20:1 to 1:1) to give 4-[(3-methylsulfonylphenyl)-(3-pyridine) as a pale yellow oil Yl)methylene]hexahydropyridine-1-carboxylic acid tert-butyl ester (400 mg, 21%). MS (ESI): m/z = 429.2 [M+H] ⁺ . c) 4-[(3 -Methylsulfonylphenyl )-(3- pyridyl ) methyl ] hexahydropyridine- 1- carboxylic acid tert-butyl ester will 4-[(3-methylsulfonyl) Phenyl)-(3-pyridyl)methylene]hexahydropyridine-1-carboxylic acid tert-butyl ester (350 mg, 0.820 mmol) and Pd/C (43 mg, 0.410 mmol) in DMF (10 mL) The mixture was stirred under H ₂ (760 mmHg) at 25°C for 16 h. The mixture was filtered and concentrated under vacuum to obtain a residue, which was purified by preparative HPLC (basic conditions) to give 4-[(3-methylsulfonylphenyl)- as a colorless oil (3-pyridyl)methyl]hexahydropyridine-1-carboxylic acid tert-butyl ester (80 mg, 23%), and the starting material (300 mg) was recovered. The recovered starting material was subjected to hydrogenation again using the same conditions as above, yielding a second batch of product as a colorless oil (110 mg, 31%). The total yield was 190 mg (54%). MS (ESI): m/z = 375.0 [MC ₄ H ₈ +H] ⁺ . d) 3-[(3- methylsulfonylphenyl )-(4- hexahydropyridyl ) methyl ] pyridine will 4-[(3-methylsulfonylphenyl)-(3-pyridyl ) Methyl) hexahydropyridine-1-carboxylic acid tert-butyl ester (220.0 mg, 0.510 mmol) and trifluoroacetic acid (0.2 mL, 2.55 mmol) in DCM (4.4 mL) was stirred at 25 °C for 4 h . The solution was concentrated under vacuum to give 3-[(3-methylsulfonylphenyl)-(4-hexahydropyridyl)methyl]pyridine (as TFA salt; 160 mg) as a colorless oil , Quantitative), which was used in the next step without further purification.

BB84 (4aR,8aS)-6-[4-[(3- methylsulfonylphenyl )-(4- pyridyl ) methyl ] hexahydropyridine- 1- carbonyl ]-4,4a,5,7 ,8,8a -hexahydropyrido [4,3-b][1,4] oxazin- 3 -one, 4-[(3-methylsulfonylphenyl)-(4-hexahydropyridyl )Methyl]pyridine (150 mg, 0.450 mmol) and (4a R ,8a S )-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3- b ] A solution of [1,4]oxazine-6-carboxylic acid (4-nitrophenyl) ester (intermediate BB15a) (219 mg, 0.680 mmol) in pyridine (6 mL) was stirred at 90°C for 16 h. The solution was concentrated under vacuum to obtain a residue, which was purified by preparative HPLC (TFA conditions) to give (4a R , 8a S )-6-[4-[(3- Methylsulfonylphenyl)-(4-pyridyl)methyl]hexahydropyridin-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3- b ] [1,4] Oxazin-3-one (60 mg, 26%). MS (ESI): m/z = 513.3 [M+H] ⁺ .

Intermediate: a) 4- [N- (p-tolyl sulfonic acyl group) -C- (pyridin-4- yl) imide carbonyl] -piperidine-1-carboxylic acid butyl ester 4- third-toluenesulfonamide Hydrazine (1.31 g, 7.03 mmol) and tert-butyl 4-(pyridine-4-carbonyl)hexahydropyridine-1-carboxylate (CAS No. 1334415-27-8) (1.70 g, 5.85 mmol) in 1, The solution in 4-dioxane (170 mL) was stirred at 80°C for 16 h. The reaction mixture was concentrated under vacuum to obtain a residue, which was purified by flash column chromatography (petroleum ether: EtOAc = 2:1) to give 4-[ N- (p-tolylsulfonate as a pale yellow solid acyl amino) - C - (4- pyridyl) imide carbonyl] -piperidine-1-carboxylic acid tert-butyl ester (1.60 g, 60%). MS (ESI): m/z = 459.2 [M+H] ⁺ . b) 4 - [(3- methyl-sulfo acyl phenyl) - (4-pyridyl) methylene] piperidine-1-carboxylic acid butyl ester third 3-bromophenyl methyl sulfone (1.23 g, 5.23 mmol), 4-[ N -(p-tolylsulfonylamino)- C -(4-pyridyl)iminocarbonyl]hexahydropyridine-1-carboxylic acid tert-butyl ester (1.60 g, 3.49 mmol), lithium tertiary butoxide (419 mg, 5.23 mmol) and bis(triphenylphosphine) palladium(II) chloride (735 mg, 1.05 mmol) in 1,4-dioxane (32 mL) The solution was stirred at 90°C for 16 h. The reaction was diluted with EtOAc (5 mL) and then filtered through celite. The filtrate was separated, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether: EtOAc = 20:1 to 1:1) to give 4-[(3-methylsulfonylphenyl)-(4-pyridyl) as a colorless oil ) Methylene] hexahydropyridine-1-carboxylic acid tert-butyl ester (420 mg, 28%). MS (ESI): m/z = 429.2 [M+H] ⁺ . c) 4-[(3 - Methylsulfonylphenyl)-(4- pyridyl ) methyl ] hexahydropyridine- 1- carboxylic acid tert-butyl ester will 4-[(3-methylsulfonyl) Phenyl)-(4-pyridyl)methylene]hexahydropyridine-1-carboxylic acid tert-butyl ester (320 mg, 0.750 mmol) and Pd/C (795 mg, 0.750 mmol) in DMF (6.4 mL) The mixture was stirred under H ₂ (760 mmHg) at 25°C for 16 h. The mixture was filtered and concentrated under vacuum to give 4-[(3-methylsulfonylphenyl)-(4-pyridyl)methyl]hexahydropyridine-1-carboxylic acid tert-butyl as a colorless oil. Ester (280 mg, 87%). MS (ESI): m/z = 431.2 [M+H] ⁺ . d) 4-[(3- methylsulfonylphenyl )-(4- hexahydropyridyl ) methyl ] pyridine will 4-[(3-methylsulfonylphenyl)-(4-pyridyl ) Methyl) hexahydropyridine-1-carboxylic acid tert-butyl ester (280 mg, 0.650 mmol) and trifluoroacetic acid (0.25 mL, 3.2 mmol) in DCM (6 mL) was stirred at 25 °C for 4 h . The solution was concentrated under vacuum to obtain a residue, which was purified by preparative HPLC (basic conditions) to obtain 4-[(3-methylsulfonylphenyl)-( as a colorless oil 4-hexahydropyridyl)methyl]pyridine (150 mg, 61%). MS (ESI): m/z = 331.2 [M+H] ⁺ .

BB85 (4aR,8aS)-6-[4-[(3- methylsulfonylphenyl )-(2- pyridyl ) methyl ] hexahydropyridine- 1- carbonyl ]-4,4a,5,7 ,8,8a -hexahydropyrido [4,3-b][1,4] oxazin- 3 -one, potassium persulfate complex salt (256 mg, 0.420 mmol) and (4a R ,8a S )- 6-[4-[(3-methylthiophenyl)-(2-pyridyl)methyl]hexahydropyridine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyridine A solution of [4,3- b ][1,4]oxazin-3-one (100 mg, 0.210 mmol) in water (5 mL) and MeCN (5 mL) was stirred at 25°C for 16 h. The solution was poured into saturated aqueous Na ₂ CO ₃ (10 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were concentrated under vacuum to obtain a residue, which was purified by preparative HPLC (TFA conditions) to give (4a R ,8a S )-6-[4-[( 3-methylsulfonylphenyl)-(2-pyridyl)methyl]hexahydropyridin-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3- b ][1,4]oxazin-3-one (60 mg, 56%). MS (ESI): m/z = 513.3 [M+H] ⁺ .

Intermediate : a) 4-[ Hydroxy- (3 -methylthiophenyl )-(2- pyridyl ) methyl ] hexahydropyridine- 1- carboxylic acid tert-butyl ester at -78°C for 0.5 h To a solution of 3-bromoanisole (1.00 mg, 4.92 mmol) in THF (30 mL) was added butyllithium solution (2.36 mL, 5.91 mmol) at the time. Then 4-(pyridine-2-carbonyl)hexahydropyridine-1-carboxylic acid tert-butyl ester (CAS number 416852-19-2) (1.43 g, 4.92 mmol) was added, and stirring was continued at -78°C for 4.5 h . The solution was quenched by saturated aqueous NH ₄ Cl (50 mL) and extracted with EtOAc (2×30 mL). The combined organic layers were concentrated under vacuum to obtain a residue, which was purified by preparative HPLC (TFA conditions) to give 4-[hydroxy-(3-methylthiophenyl) as a colorless oil -(2-pyridyl)methyl]hexahydropyridine-1-carboxylic acid tert-butyl ester (1.40 g, 69%). MS (ESI): m/z = 415.2 [M+H] ⁺ . b) 2-[ chloro- (3 -methylthiophenyl )-(4- hexahydropyridyl ) methyl ] pyridine will 4-[hydroxy-(3-methylthiophenyl)-(2- Pyridyl)methyl) hexahydropyridine-1-carboxylic acid tert-butyl ester (300 mg, 0.720 mmol) and sulfur dichloride (86 mg, 0.72 mmol) in Tol (5 mL) under N ₂ Stir at 25 °C for 6 h. The mixture was concentrated under vacuum to give 2-[chloro-(3-methylthiophenyl)-(4-hexahydropyridyl)methyl]pyridine (220 mg, 91%) as a yellow solid, which Used as crude material in the next step. MS (ESI): m/z = 333.1 [M+H] ⁺ . c) 2-[(3 -methylthiophenyl )-(4- hexahydropyridyl ) methyl ] pyridine will 2-[chloro-(3-methylthiophenyl)-(4-hexahydro Pyridyl)methyl)pyridine (220 mg, 0.660 mmol), ammonium chloride (35 mg, 0.66 mmol) and zinc (238 mg, 3.64 mmol) in MeOH (6 mL) were stirred at 25°C for 0.5 h . The mixture was filtered and concentrated under vacuum to obtain a residue, which was purified by preparative HPLC (basic conditions) to give 2-[(3-methylthiophenyl)-( as a colorless oil 4-hexahydropyridyl)methyl]pyridine (160 mg, 81%). MS (ESI): m/z = 299.1 [M+H] ⁺ . d) (4aR,8aS)-6-[4-[(3 -methylthiophenyl )-(2- pyridyl ) methyl ] hexahydropyridine- 1- carbonyl ]-4,4a,5,7 ,8,8a -hexahydropyrido [4,3-b][1,4] oxazin- 3 -one 2-((3-methylthiophenyl)-(4-hexahydropyridyl) Methyl]pyridine (160 mg, 0.540 mmol) and (4a R ,8a S )-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3- b ][ A solution of 1,4]oxazine-6-carboxylic acid (4-nitrophenyl) ester (intermediate BB15a) (207 mg, 0.640 mmol) in pyridine (10 mL) was stirred at 90°C for 16 h. The solution was filtered and concentrated under vacuum to obtain a residue, which was purified by preparative HPLC (TFA conditions) to give (4a R , 8a S )-6-[4-[(3- (Methylthiophenyl)-(2-pyridyl)methyl]hexahydropyridin-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3- b ][ 1,4] Oxazin-3-one (200 mg, 78%). MS (ESI): m/z = 481.2 [M+H] ⁺ .

BB86 3-[ phenyl (4- hexahydropyridyl ) methyl ] pyrazine hydrochloride, 4-[phenyl(pyrazin-3-yl)methyl]hexahydropyridine-1-carboxylic acid tert-butyl A solution of the ester (150 mg, 0.420 mmol) and trifluoroacetic acid (0.1 mL, 1.3 mmol) in DCM (3 mL) was stirred at 25°C for 4 h. The solution was concentrated under vacuum to obtain a residue, which was purified by preparative HPLC (HCl condition) to give 3-[phenyl(4-hexahydropyridyl)methyl]pyrazine ( In the form of HCl salt, 70 mg, quantitative). MS (ESI): m/z = 254.2 [M+H] ⁺ .

Intermediate : 4-( chloro - phenyl - pyrazin- 3 -yl - methyl ) hexahydropyridine- 1- carboxylic acid tert-butyl ester 4-(pyrazin-3-carbonyl)hexahydropyridine-1- A solution of tert-butyl formate (CAS No. 2044281-15-2) (250 mg, 0.860 mmol) and phenylmagnesium bromide (3 M, 0.34 mL, 1.03 mmol) in THF (6 mL) in N ₂ Stir at 0 °C for 3 h. The solution was poured into brine (20 mL) and extracted with EtOAc (20 mL). The organic layer was concentrated under vacuum to obtain a residue, which was purified by preparative HPLC (TFA conditions) to obtain 4-(hydroxy-phenyl-oxazin-3-yl-methyl)hexanol as a gray solid Tert-butyl hydropyridine-1-carboxylate (200 mg, 63%). MS (ESI): m/z = 314.1 [MC ₄ H ₈ +H] ⁺ . 4-( chloro - phenyl - oxazin- 3 -yl - methyl ) hexahydropyridine- 1- carboxylic acid tert-butyl ester will 4-(hydroxy-phenyl-oxazin-3-yl-methyl)hexa A mixture of tert-butyl hydropyridine-1-carboxylate (200 mg, 0.520 mmol) and sulfur dichloride (306 mg, 2.59 mmol) in Tol (10 mL) was stirred at 25°C for 6 h. The mixture was filtered and concentrated under vacuum to give 4-(chloro-phenyl-pyrazin-3-yl-methyl)hexahydropyridine-1-carboxylic acid tert-butyl ester (200 mg, 99%) as a yellow solid ), which is used as crude material in the next step. MS (ESI): m/z = 410.2 [M+Na] ⁺ . 4-[ Phenyl ( triazin- 3 -yl ) methyl ] hexahydropyridine- 1- carboxylic acid tert-butyl ester 4-(chloro-phenyl-pyrazin-3-yl-methyl)hexahydropyridine A solution of tert-butyl-1-carboxylate (200 mg, 0.52 mmol), ammonium chloride (28 mg, 0.52 mmol) and zinc (185 mg, 2.84 mmol) in MeOH (4.7 mL) was stirred at 25°C 0.5 h. The mixture was concentrated under vacuum to give a residue, which was purified by preparative HPLC (TFA conditions) to give 4-[phenyl(oxazin-3-yl)methyl]hexahydropyridine as a yellow solid 3-Butyl 1-formate (150 mg, 82%). MS (ESI): m/z = 298.1 [MC ₄ H ₈ +H] ⁺ .

BB87 3-[4-(3- fluoropropyl ) phenyl ] azetidine will 3-[4-(3-fluoropropyl)phenyl]azetidine-1-carboxylic acid tert-butyl A solution of the ester (80 mg, 0.27 mmol) and trifluoroacetic acid (0.07 mL, 0.85 mmol) in DCM (2 mL) was stirred at 25°C for 4 h. The mixture was concentrated under vacuum to give 3-[4-(3-fluoropropyl)phenyl]azetidine (40 mg, 76%) as a colorless oil, which was used as is in the next step . MS (ESI): m/z = 194.1 [M+H] ⁺ .

酸 向2-[4-(3-氟丙基)苯基]-4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷(600 mg, 2.27 mmol)於H₂ O (12 mL)及丙酮(60 mL)中之溶液添加HCl (1M, 1 mL)。將溶液在25℃下攪拌16 h。將該溶液傾倒至鹽水(40 mL)中並用EtOAc (2 × 20 mL)萃取。將合併之有機層在真空下濃縮，得到呈淺黃色固體之[4-(3-氟丙基)苯基]

酸(300 mg, 73%)。¹ H NMR (400 MHz，氯仿-d)δ = 8.19 (d,J =7.9 Hz, 2H), 7.37 (d,J =7.8 Hz, 2H), 4.52 (dt,J =47.2, 5.9 Hz, 2H), 2.87 (t,J =7.1 Hz, 2H), 2.16 - 2.02 (m, 2H)。c) 3-[4-(3- 氟丙基 ) 苯基 ] 氮雜環丁烷 -1- 甲酸第 三丁基 酯 於密封管中將[4-(3-氟丙基)苯基]

酸(145 mg, 0.790 mmol)、3-碘氮雜環丁烷-1-甲酸第三丁基酯(CAS編號254454-54-1) (150 mg, 0.530 mmol)、碘化鎳(II)(99 mg, 0.32 mmol) (1S ,2S )-2-胺基環己醇(37 mg, 0.32 mmol)及雙(三甲基矽基)胺化鈉(1.06 mL, 1.06 mmol)於2-丙醇(4 mL)中之溶液在80℃下攪拌1 h。將混合物過濾並在真空下濃縮以得到殘餘物，藉由製備型HPLC (TFA條件)純化該殘餘物，產生呈無色油狀物之3-[4-(3-氟丙基)苯基]氮雜環丁烷-1-甲酸第三丁基酯(82 mg, 46%)。MS (ESI): m/z = 238.1 [M-C₄ H₈ +H]⁺ 。 Intermediate: a) 2- [4- (3- fluoropropyl) phenyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane 1- Bromo-4-(3-fluoropropyl)benzene (CAS No. 168104-62-9) (1.00 g, 4.61 mmol), bis(pinacol) diboron (2.34 g, 9.21 mmol), (Pd(dppf) Cl ₂ ]∙CH ₂ Cl ₂ (376 mg, 0.460 mmol) and KOAc (1.35 g, 13.8 mmol) in 1,4-dioxane (40 mL) were stirred under N ₂ at 100°C for 16 h . The mixture was filtered and concentrated to obtain a residue, which was purified by flash column chromatography (petroleum ether: EtOAc = 10:1) to give 2-[4-(3-fluoropropyl) as a colorless oil )Phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.2 g, 99%). MS (ESI): m/z = 265.1 [M+H] ⁺ . b) [4-(3- fluoropropyl ) phenyl ]

Acid 2- [4- (3-fluoropropyl) phenyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane (600 mg, 2.27 mmol ) A solution in H ₂ O (12 mL) and acetone (60 mL) was added HCl (1M, 1 mL). The solution was stirred at 25°C for 16 h. The solution was poured into brine (40 mL) and extracted with EtOAc (2×20 mL). The combined organic layer was concentrated under vacuum to give [4-(3-fluoropropyl)phenyl] as a light yellow solid

Acid (300 mg, 73%). ¹ H NMR (400 MHz, chloroform-d) δ = 8.19 (d, J = 7.9 Hz, 2H), 7.37 (d, J = 7.8 Hz, 2H), 4.52 (dt, J = 47.2, 5.9 Hz, 2H) , 2.87 (t, J =7.1 Hz, 2H), 2.16-2.02 (m, 2H). C) 3- [4- (3-fluoropropyl) phenyl] azetidine-1-carboxylic acid butyl ester in the third sealed tube [4- (3-fluoropropyl) phenyl]

Acid (145 mg, 0.790 mmol), tert-butyl 3-iodoazetidine-1-carboxylate (CAS No. 254454-54-1) (150 mg, 0.530 mmol), nickel(II) iodide ( 99 mg, 0.32 mmol) (1 S ,2 S )-2-aminocyclohexanol (37 mg, 0.32 mmol) and sodium bis(trimethylsilyl)amide (1.06 mL, 1.06 mmol) in 2- The solution in propanol (4 mL) was stirred at 80°C for 1 h. The mixture was filtered and concentrated under vacuum to obtain a residue, which was purified by preparative HPLC (TFA conditions) to give 3-[4-(3-fluoropropyl)phenyl] nitrogen as a colorless oil Heterocyclobutane-1-carboxylic acid tert-butyl ester (82 mg, 46%). MS (ESI): m/z = 238.1 [MC ₄ H ₈ +H] ⁺ .

BB88 2-( azetidin- 3 -yl )-5-(2,4- dichlorophenyl )-1,3,4 -oxadiazole compound 3-[[(2,4-dichlorobenzene Methyl)amino]aminemethyl]azetidine-1-carboxylic acid tert-butyl ester (800.0 mg, 2.06 mmol) was suspended in polyphosphoric acid (5 mL), and the mixture was stirred at 180°C 2 h. The mixture was poured into glacial ammonia (100 mL), stirred for 10 min, then extracted three times with EtOAc (100 mL each time), the combined organic phases were washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by reverse phase flash column chromatography (0.1% v/v FA) to give the desired product (130 mg, 17%) as a light brown oil. MS (ESI): m/z = 270.4 [M+H] ⁺ .

Intermediate: 3-[[(2,4- Dichlorobenzyl ) amino ] aminomethylamino ] azetidine- 1- carboxylic acid third butyl ester to 1-Boc-azetidine Alkane-3-carboxylic acid (490.68 mg, 2.44 mmol, CAS RN 142253-55-2) and 2,4-dichlorophenylhydrazide (500.0 mg, 2.44 mmol, CAS RN 5814-06-2), DIPEA (1.27 mL , 7.32 mmol) in DMF (20 mL) was added T ₃ P (1122.42 mg, 4.88 mmol, 50% in EtOAc), and the mixture was stirred at 80° C. for 12 h. The mixture was diluted with EtOAc (50 mL), washed with NaHCO ₃ (100 mL) and brine, then dried over Na ₂ SO ₄ and evaporated to give the crude product (800 mg, 84.5%) as a light brown oil. MS (ESI): m/z = 332.4 [MC ₄ H ₈ +H] ⁺ .

BB89 3-( azetidin- 3 -yl )-1-(2,4- dichlorophenyl ) pyrazole trifluoroacetate to 3-[1-(2,4-dichlorophenyl)pyrazole 3-yl]azetidine-1-carboxylic acid tert-butyl ester (350.0 mg, 0.950 mmol) in DCM (5 mL) was added TFA (1.0 mL, 0.950 mmol), and the mixture was added at 20 Stir for 12 h at ℃. The mixture was concentrated to give the desired product (350 mg, 96.4%) as a yellow oil. MS (ESI): m/z = 268.1 [M+H] ⁺ .

Intermediate : a) 3-[ Methoxy ( methyl ) aminecarboxamide ] azetidine- 1- carboxylic acid third butyl ester to 1-BOC-azetidine-3-carboxylic acid (10.0 g, 49.7 mmol, CAS RN 142253-55-2) in DCM (200 mL) was added CDI (8.06 g, 49.7 mmol), the mixture was stirred at 20°C for 1 h, and then TEA (13.85 mL, 99.39 mmol) and O,N-dimethylhydroxylamine HCl salt (5.82 g, 59.64 mmol, CAS RN 6638-79-5), the mixture was stirred at 20°C for 15 h, and then washed with Na ₂ CO ₃ aqueous solution and brine The mixture was dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated to give the crude product (12 g) as a pale yellow oil, which was used in the next step without further purification. b) 3-Ethyl azetidine- 1- carboxylic acid tert-butyl ester at 0°C to 3-[methoxy(methyl)aminemethylacetoyl]azetidine-1-carboxylic acid A solution of the third butyl ester (1000.0 mg, 4.09 mmol) in THF (30 mL) was added MeMgBr/THF (1.77 mL, 3M), the mixture was stirred at 20°C for 2 h, and then the mixture was poured to saturated NH ₄ Cl solution (100 mL) and extracted with EtOAc (30 mL, three times), the combined organic phases were washed with brine, dried over Na ₂ SO ₄ and concentrated to give the desired product (810 mg, 99.3) as a pale yellow oil %). ¹ H NMR (400 MHz, chloroform-d) δ = 4.05 (br d, J = 7.4 Hz, 4H), 3.48-3.34 (m, 1H), 2.18 (d, J = 2.0 Hz, 2H), 1.44 (d , J = 2.0 Hz, 9H). c) 3 - [(E) -3- ( dimethylamino) prop-2-en-acyl] azetidine-1-carboxylic acid butyl ester 3-third acetylsalicylic azetidin A solution of alkane-1-carboxylic acid tert-butyl ester (500.0 mg, 2.51 mmol) in N,N-dimethylformamide dimethyl acetal (10.0 mL) was stirred at 110°C for 12 h, and the mixture Concentrate to give the title compound (640 mg, 2.52 mmol) as a yellow oil. MS (ESI): m/z = 199.2 [MC ₄ H ₈ +H] ⁺ . d) 3-[1-(2,4- dichlorophenyl ) pyrazol- 3 -yl ] azetidine- 1- carboxylic acid tert-butyl ester 3-((E)-3-(di Methylamino) prop-2-enyl] azetidine-1-carboxylic acid tert-butyl ester (500.0 mg, 1.97 mmol) and 2,4-dichlorobenzohydrazide hydrochloride (474.78 mg, 1.97 mmol) in EtOH (30 mL) was stirred at 80°C for 12 h, the mixture was concentrated, and the residue was purified by a silica gel column (PE: EtOAc = 20: 1 to 3: 1) to obtain The desired product (450 mg, 62.2%) as a yellow oil. MS (ESI): m/z = 368.1 [M+H] ⁺ .

BB90 3-[4-(2,2 -dimethylpropyl ) phenyl ] azetidine trifluoroacetate to 3-[4-(2,2-dimethylpropyl)phenyl]nitrogen A solution of tert-butyl heterocyclobutane-1-carboxylate (500.0 mg, 1.65 mmol) in DCM (10 mL) was added TFA (2.0 mL), and the mixture was stirred at 20° C. for 12 h. The mixture was concentrated to give the crude product (520 mg) as a light yellow oil. MS (ESI): m/z = 204.2 [M+H] ⁺ .

Intermediate : a) 1- Bromo- 4-(2,2 -dimethylpropyl ) benzene to 2,2-dimethylpropylbenzene (500.0 mg, 3.37 mmol, CAS RN 1007-26-7) Bromine (0.17 mL, 3.37 mmol) was added to the solution in acetic acid (10 mL). The mixture was stirred in the dark at 20 °C for 12 h, and then the mixture was poured into saturated aqueous Na ₂ SO ₃ (30 mL) and extracted three times with EtOAc (10 mL each time). The combined organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated to give the crude product (600 mg, 78.3%) as a pale yellow oil, which was used in the next step without further purification. b) 3-[4-(2,2 -Dimethylpropyl ) phenyl ] azetidine- 1- carboxylic acid tert-butyl ester Add 3-bromoaza to a 40 mL vial equipped with a stir bar Tert-butyl cyclobutane-1-carboxylate (519.75 mg, 2.2 mmol, CAS RN 1064194-10-0), 1-bromo-4-(2,2-dimethylpropyl)benzene (500.0 mg, 2.2 mmol), Ir[dF(CF ₃ )ppy] ₂ (dtbbpy)PF ₆ (24.68 mg, 0.020 mmol, CAS RN 870987-63-6), NiCl ₂ glyme (2.42 mg, 0.010 mmol, CAS RN 29046-78 -4), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (3.54 mg, 0.010 mmol, CAS RN 69641-93-6), bis(trimethylsilyl ) Silyl-trimethyl-silane (547.37 mg, 2.2 mmol, CAS RN 1873-77-4) and Na ₂ CO ₃ (466.63 mg, 4.4 mmol), then add DME (20 mL). The vial was sealed and placed under nitrogen. The reaction mixture was stirred and irradiated with a 34 W blue LED lamp (7 cm distance), and the reaction temperature was maintained at 25°C for 14 h using a cooling fan. The mixture was filtered and the filtrate was concentrated. The residue was purified by reverse phase flash chromatography (0.1% v/v FA) to give the desired product (500 mg, 74.8%) as a pale yellow oil. MS (ESI): m/z = 248.2 [MC ₄ H ₈ +H] ⁺ .

BB91 (4aR,8aS)-6-[3-[4-(4,4,5,5 -tetramethyl -1,3,2- dioxaborolane -2- yl ) phenyl ] Azetidine- 1- carbonyl ]-4,4a,5,7,8,8a -hexahydropyrido [4,3-b][1,4] oxazin- 3 -one to (4aR,8aS )-6-[3-(4-Bromophenyl)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1 , 4) oxazin-3-one (200.0 mg, 0.510 mmol, Example 110) and PdCl ₂ (dppf)·DCM (35.56 mg, 0.050 mmol) solution was added potassium acetate (149.36 mg, 1.52 mmol) and bis (frequency Naphthol) diboron (193.23 mg, 0.760 mmol), the reaction mixture was purged with nitrogen and stirred at 90 °C for 12 h. The reaction mixture was diluted with water and extracted three times with EtOAc. The combined organic layer was washed with water and brine, dried over sodium sulfate and concentrated in vacuo to obtain a yellow residue, which was purified by reverse phase flash chromatography (0.1% v/v FA) to provide a pale yellow color Solid desired product (140 mg, 0.320 mmol, 62.5%). MS (ESI): m/z = 442.3 [M+H] ⁺ .

BB92 2- bromo-ethyl-5-methyl -N- - benzoyl-5-methyl-amine 2-bromo-benzoic acid (500.0 mg, 2.33 mmol, CAS RN 6967-82-4) and HOBT (534.11 mg , 3.49 mmol), EDCI (541.43 mg, 3.49 mmol) and DIPEA (1.21 mL, 6.98 mmol) in DMF (10 mL) were added ethylamine hydrochloride (227.51 mg, 2.79 mmol), and the mixture was added at 20 Stir for 12 h at ℃. The mixture was then poured into saturated aqueous Na ₂ CO ₃ (50 mL) and extracted three times with EtOAc (20 mL each time). The combined organic layer was washed with brine and dried over Na ₂ SO ₄ and concentrated to give the desired product (450 mg, 79.9%) as a light yellow solid. MS (ESI): m/z = 242.0 [M+H] ⁺ .

BB93 Azetidine -3- Base pair (4- Fluorophenyl ) Methanol A dry 100 mL double-necked round bottom flask equipped with a reflux condenser was charged with THF (18.6 mL) and 3-methylazetidine-1,3-dicarboxylic acid 1-(third butyl) under argon Ester (800 mg, 746 µL, 3.72 mmol, CAS RN 610791-05-4). The mixture was purged with argon for 5 min and cooled to 0°C. Then, a 0.8 M (4-fluorophenyl) magnesium bromide solution (18.6 mL, 14.9 mmol) in THF was added over 10 min. After the addition was complete, the reaction mixture was heated to 85 °C (oil bath) for 17 h. The reaction was quenched with water (5 mL), diluted with EtOAc (10 mL), and the resulting slurry was stirred for 15 min. Water was added and the mixture was acidified with 2 M HCl (20 mL) until the aqueous phase became a colorless solution. The phases were separated, and the aqueous phase was extracted with EtOAc (100 mL). The pH was adjusted to 7, and the aqueous phase was extracted four times with EtOAc. The combined organic layer was concentrated to about 50 mL. A precipitate formed and the flask was cooled to 4°C. The precipitate was filtered and the white solid was washed with a small portion of EtOAc to give the title compound (317 mg, 31%). MS (ESI): m/z = 276.2 [M+H]⁺ .

BB94 3-(1-(2- chloro- 4-( trifluoromethyl ) phenoxy ) ethyl ) azetidine 2,2,2- trifluoroacetate trifluoroacetic acid (400 mg, 270 µL, 3.51 mmol) added to 3-(1-(2-chloro-4-(trifluoromethyl)phenoxy)ethyl)azetidine-1-carboxylic acid tert-butyl ester (78.4 mg, 206 µmol) in DCM (1.03 mL), and the solution was stirred at room temperature for 2 h. The solvent was removed under reduced pressure to give the compound as a light yellow oil (134 mg, 100%. The crude product was used in the next step without further purification. MS (ESI): m/z = 280.1 [M +H] ⁺ .

Intermediate 3-(1-(2- chloro- 4-( trifluoromethyl ) phenoxy ) ethyl ) azetidine- 1- carboxylic acid tert-butyl ester at 0 °C to 2-chloro- 4-(trifluoromethyl)phenol (500 mg, 340 µL, 2.54 mmol), 3-(1-hydroxyethyl)azetidine-1-carboxylic acid tert-butyl ester (512 mg, 2.54 mmol, CAS RN 1138331-90-4) and triphenylphosphine (734 mg, 2.8 mmol) in DCM (12.7 mL) were added DIAD (566 mg, 544 µL, 2.8 mmol) dropwise, and the reaction was carried out at 0 °C Stir for 10 min and stir at room temperature for 6 h. The reaction mixture was quenched by the addition of saturated aqueous NaHCO ₃ (20 mL). The phases were separated, and the aqueous phase was extracted twice with DCM. The combined organic layer was dried over Na ₂ SO ₄ , filtered and stored at 4° C. for four days. The crude product was concentrated to dryness, fixed on Isolute® and purified by flash column chromatography (for gradient elution of 0% to 30% EtOAc in n-heptane) to give the title compound as a pale oil. (497 mg, 48.9%). MS (ESI): m/z = 324.1 [MC ₄ H ₈ +H] ⁺ .

BB95 4-(1-(2- chloro- 4- fluorophenoxy )-2,2,2- trifluoroethyl ) hexahydropyridine hydrochloride hydrochloride (4 M in dioxane) (174 µL , 695 µmol) added to 4-(1-(2-chloro-4-fluorophenoxy)-2,2,2-trifluoroethyl)hexahydropyridine-1-carboxylic acid tert-butyl ester (17.9 mg , 43.5 µmol) in dioxane (435 µL), and the solution was stirred at room temperature for 2 h. The solvent was removed under reduced pressure to obtain the desired compound (15 mg, 95%) as a pale yellow oil. The crude product was used in the next step without further purification. MS (ESI): m/z = 312.1 [M+H] ⁺ .

Intermediate a) 4-(1-(2- chloro- 4- fluorophenoxy )-2,2,2- trifluoroethyl ) hexahydropyridine- 1- carboxylic acid tert-butyl ester 4-(2 , 2,2-trifluoro-1-(((trifluoromethyl)sulfonyl)oxy)ethyl) hexahydropyridine-1-carboxylic acid tert-butyl ester (126 mg, 303 µmol), 2- Chloro-4-fluorophenol (48.9 mg, 36.4 µL, 334 µmol) and cesium carbonate (109 mg, 334 µmol) were suspended in DMF (1.52 mL) and stirred at room temperature for 20 h. The reaction mixture was then quenched with water and extracted twice with EtOAc. The combined organic phases were washed with water and brine, dried over MgSO ₄ and concentrated in vacuo. The residue was fixed on Isolute® and purified by flash column chromatography (0% to 30% EtOAc gradient in n-heptane) to give the title compound (20 mg, 15%) as a colorless oil ). MS (ESI): m/z = 356.1 [MC ₄ H ₈ +H] ⁺ . b) 4-(2,2,2- trifluoro -1-((( trifluoromethyl ) sulfonyl ) oxy ) ethyl ) hexahydropyridine- 1- carboxylic acid tert-butyl ester in a microwave vial Loaded with tert-butyl 4-(2,2,2-trifluoro-1-hydroxyethyl)hexahydropyridine-1-carboxylate (100 mg, 353 µmol, CAS RN 184042-83-9). The vial was placed under argon, DCM (1.76 mL) was added and cooled to 0 °C. Pyridine (33.5 mg, 34.3 µL, 424 µmol) was added, followed by trifluoromethanesulfonic anhydride (110 mg, 65.6 µL, 388 µmol). The reaction mixture was stirred at 0 °C for 1 h, and then quenched with water. The mixture was separated, and the organic phase was washed with water and extracted three times with DCM. The combined organic layer was washed with brine, dried over MgSO ₄ and concentrated in vacuo to give the desired compound (126 mg, 85.9%) as a yellow oil. This compound was used in the next step without further purification.

BB96 3-( bis (4- fluorophenyl ) methyl ) azetidine Combine 3-( bis (4- fluorophenyl ) methylene ) azetidine (20 mg, 77.7 µmol) in MeOH The solution in (777 µL) was evacuated and backfilled with argon five times. Under an argon atmosphere, Pd-C (4.14 mg, 3.89 µmol) was added, and the atmosphere was replaced with hydrogen three times. The reaction was stirred under a 1 bar hydrogen atmosphere (balloon) for 19 h. The atmosphere was replaced with argon, and the reaction mixture was filtered through a pad of celite. The filter cake was washed with MeOH. The filtrate was concentrated to give the desired compound (20.1 mg, 94.7%) as a yellow solid, which was used in the next step without further purification. MS (ESI): m/z = 260.2 [M+H] ⁺ .

Intermediate 3-( bis (4- fluorophenyl ) methylene ) azetidine to azetidine-3-ylbis(4-fluorophenyl)methanol (244 mg, 886 µmol, BB93) at The suspension in DCM (2.22 mL) was added TFA (2.22 mL), and the mixture was stirred for 3.5 h. This gives a homogeneous solution. The reaction was evaporated to dryness, the resulting residue was diluted with EtOAc, washed twice with saturated aqueous sodium bicarbonate, then twice with brine, dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated to dryness in vacuo, and the residue was triturated with EtOAc/n-heptane and filtered. This gave the title compound (20 mg, 8.3%) as a white solid. MS (ESI): m/z = 258.2 [M+H] ⁺ .

BB97 3-(1-(2- fluoro- 4-( trifluoromethyl ) phenoxy ) ethyl ) azetidine 2,2,2- trifluoroacetic acid salt to 3-(1-(2- Fluoro-4-(trifluoromethyl)phenoxy)ethyl)azetidine-1-carboxylic acid tert-butyl ester (93 mg, 256 µmol) in DCM (1 mL) was added 2, 2,2-trifluoroacetic acid (467 mg, 316 µL, 4.1 mmol), and the reaction was stirred at room temperature for 20 h. The reaction mixture was concentrated to give the desired compound (112.8 mg, 99%) as a colorless oil, which was used in the next step without further purification. MS (ESI): m/z = 264.1 [M+H] ⁺ .

Intermediate a) 3-(1-(2- fluoro- 4-( trifluoromethyl ) phenoxy ) ethyl ) azetidine- 1- carboxylic acid tert-butyl ester to 2-fluoro-4- (Trifluoromethyl)phenol (100 mg, 69.9 µL, CAS RN 77227-78-2), 3-(1-hydroxyethyl)azetidine-1-carboxylic acid tert-butyl ester (112 mg, A solution of 555 µmol, CAS RN 1138331-90-4) and triphenylphosphine (160 mg, 611 µmol) in DCM (2.8 mL) was added DIAD (124 mg, 119 µL, 611 µmol) dropwise, and the reaction Stir at room temperature for 1.5 h. The reaction mixture was quenched by adding saturated aqueous NaHCO ₃ solution. The phases were separated and the aqueous phase was extracted with DCM. The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was fixed on Isolute and purified by flash column chromatography (0% to 20% EtOAc gradient in n-heptane) to give the desired compound as a colorless oil (93 mg, 43.8%) . MS (ESI): m/z = 308.1 [MC ₄ H ₈ +H] ⁺ .

BB98 3-(1-(4- trifluoromethyl ) phenoxy ) ethyl ) azetidine 2,2,2- trifluoroacetate is similar to BB97, BB98 is derived from 4-(trifluoromethyl ) Phenol and 3-(1-hydroxyethyl)azetidine-1-carboxylic acid third butyl ester are produced. This compound was used in the next step without further purification.

BB99 (S or R)-4-((4- fluorophenyl )(3 -methoxyphenyl ) methyl ) hexahydropyridine is separated by SFC to 4-((4-fluorophenyl)-(3 -Methoxyphenyl)methyl]hexahydropyridine (760 mg, 2.54 mmol) in MeOH (5 mL) was purified to give 4-[(S or R)-(4 -Fluorophenyl)-(3-methoxyphenyl)methyl]hexahydropyridine (128 mg, 0.43 mmol, 17%); MS (ESI): m/z = 300.1 [M+H] ⁺ ; and 4-[(R or S)-(4-fluorophenyl)-(3-methoxyphenyl)methyl]hexahydropyridine (170 mg, 0.57 mmol, 22%) as a light yellow semi-solid; MS (ESI): m/z = 300.1 [M+H] ⁺ .

Intermediate a) 4-[(4- fluorophenyl )( hydroxy )(3 -methoxyphenyl ) methyl ] hexahydropyridine- 1- carboxylic acid tert-butyl ester at -78°C to 3-bromo To a solution of anisole (487 mg, 2.6 mmol) in THF (40 mL) was added butyllithium (1.5 mL, 3.75 mmol, 2.5 M). After stirring for 1 h, tert-butyl 4-(4-fluorobenzyl)hexahydropyridine-1-carboxylate (CAS RN 160296-40-2; 800 mg, 2.6 mmol) was added to the mixture at- Continue stirring at 78 °C for 1 h. The reaction was then warmed to 25°C and stirred for another 13 h. The reaction was quenched with NH ₄ Cl (saturated aqueous solution, 50 mL) and extracted with EtOAc (100 mL). The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to give the desired compound (1100 mg, 63%) as a yellow oil. MS (ESI): m/z = 438.1 [M+Na] ⁺ . b) 4-[(4- fluorophenyl )(3 -methoxyphenyl ) methylene ] hexahydropyridine trifluoroacetate will 4-((4-fluorophenyl)(hydroxy)(3-methyl Oxyphenyl)methyl]hexahydropyridine-1-carboxylic acid tert-butyl ester (1.1 g, 1.64 mmol) and trifluoroacetic acid (5.0 mL, 65 mmol) in DCM (10 mL) at 25°C Stir for 5 h. The reaction was concentrated under vacuum. The residue was dissolved in EtOAc (50 mL) and washed with Na ₂ CO ₃ (aq, 10%, 50 mL). The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum. Purify the resulting oil by preparative HPLC (TFA as an additive) to obtain 4-[(4-fluorophenyl)(3-methoxyphenyl)methylene]hexahydropyridine (TFA salt) as a white solid , 430 mg, 39%). MS (ESI): m/z = 298.1 [M+H] ⁺ . c) 4-[(4- fluorophenyl )(3 -methoxyphenyl ) methyl ] hexahydropyridine trifluoroacetate will 4-[(4-fluorophenyl)(3-methoxyphenyl )Methylene)hexahydropyridine (410 mg, 1.38 mmol) and Pd/C (100 mg, 1.38 mmol) in THF (10 mL) were stirred under H ₂ (760 mm Hg) at 25°C for 16 h. The reaction mixture was filtered through diatomaceous earth and then concentrated under vacuum to give 4-[(4-fluorophenyl)(3-methoxyphenyl)methyl]hexahydropyridine (TFA salt, as a yellow oil, 260 mg, 59%). MS (ESI): m/z = 300.1 [M+H] ⁺ .

BB100 (R or S)-4-((4- fluorophenyl )(3 -methoxyphenyl ) methyl ) hexahydropyridine is separated by SFC to 4-((4-fluorophenyl)-(3 -Methoxyphenyl)methyl]hexahydropyridine (BB99, intermediate c, 760 mg, 2.54 mmol) in MeOH (5 mL) was purified to give 4-[(S Or R)-(4-fluorophenyl)-(3-methoxyphenyl)methyl]hexahydropyridine (128 mg, 17%); LCMS: 300.1 [M+H] ⁺ ; and light yellow half 4-[(R or S)-(4-fluorophenyl)-(3-methoxyphenyl)methyl]hexahydropyridine or 4-[(S)-(4-fluorophenyl)- (3-methoxyphenyl)methyl]hexahydropyridine (170 mg, 22%); MS (ESI): m/z = 300.1 [M+H] ⁺ .

BB101 (S or R)-4-((3 -methoxyphenyl )( phenyl ) methyl ) hexahydropyridine was purified by preparative HPLC using TFA as additive 4-[(3-methoxyphenyl )-Phenyl-methyl]hexahydropyridine (960 mg, 3.41 mmol) in MeOH (5 mL) to give 4-[-(3-methoxyphenyl)-benzene as its TFA salt -Methyl] hexahydropyridine (1260 mg). Purification of 4-[-(3-methoxyphenyl)-phenyl-methyl]hexahydropyridine TFA salt (1260 mg) by SFC separation to give (S or R)-4 as a pale yellow solid -((3-methoxyphenyl)(phenyl)methyl)hexahydropyridine (443 mg, 45%); MS (ESI): m/z = 282.2 [M+H] ⁺ ; and yellow solid Of (R or S)-4-((3-methoxyphenyl)(phenyl)methyl)hexahydropyridine (383 mg, 39%); MS (ESI): m/z = 282.2 [M+ H] ⁺ .

Intermediate 4-((3 -methoxyphenyl )( phenyl ) methyl ) hexahydropyridine The title compound is similar to intermediate 1-[(4-fluorophenyl)-phenyl-methyl]hexahydro Pyrazine (CAS RN 27064-89-7), prepared starting from 3-bromoanisole and tert-butyl 4-benzylhexahydropyridine-1-carboxylate (CAS RN 922504-27-6), The title compound was obtained as a light yellow semi-solid. MS (ESI): m/z = 282.1 [M+H] ⁺ .

BB102 (R or S)-4-((3 -methoxyphenyl )( phenyl ) methyl ) hexahydropyridine was purified by preparative HPLC using TFA as additive 4-[(3-methoxyphenyl )-Phenyl-methyl]hexahydropyridine (BB101, intermediate, 960 mg, 3.41 mmol) in MeOH (5 mL) to give 4-[-(3-methoxy) as its TFA salt Phenyl)-phenyl-methyl]hexahydropyridine (1260 mg). Purification of 4-[-(3-methoxyphenyl)-phenyl-methyl]hexahydropyridine TFA salt (1260 mg) by SFC separation to give (S or R)-4 as a pale yellow solid -((3-methoxyphenyl)(phenyl)methyl)hexahydropyridine (443 mg, 45%); MS (ESI): m/z = 282.2 [M+H] ⁺ ; and yellow solid Of (R or S)-4-((3-methoxyphenyl)(phenyl)methyl)hexahydropyridine (383 mg, 39%); MS (ESI): m/z = 282.2 [M+ H] ⁺ .

BB103 (S or R)-4-((3-(2- fluoroethoxy ) phenyl )( phenyl ) methyl ) hexahydropyridine is separated by SFC to 4-[[3-(2-fluoroethyl Oxy)phenyl]-phenyl-methyl]hexahydropyridine (800 mg, 2.55 mmol) in MeOH (5 mL) for purification to give (S or R)-4-(( 3-(2-fluoroethoxy)phenyl)(phenyl)methyl)hexahydropyridine (214 mg, 27%); MS (ESI): m/z = 314.1 [M+H] ⁺ ; and (R or S)-4-((3-(2-fluoroethoxy)phenyl)(phenyl)methyl)hexahydropyridine (305 mg, 38%) as a white solid; MS (ESI): m /z = 314.1 [M+H] ⁺ .

Intermediate 4-((3-(2- fluoroethoxy ) phenyl )( phenyl ) methyl ) hexahydropyridine The title compound is similar to intermediate 1-[(4-fluorophenyl)-phenyl- Methyl] hexahydropyrazine (CAS RN 27064-89-7), from 1-bromo-3-(2-fluoroethoxy)benzene (CAS RN 132837-02-6) and 4-benzyl hexamethylene The preparation of the third butyl hydropyridine-1-carboxylate (CAS RN 922504-27-6) gave the title compound as a colorless oil. MS (ESI): m/z = 314.1 [M+H] ⁺ .

BB104 (S or R)-4-((4- fluorophenyl )( phenyl ) methyl ) hexahydropyridine is separated by SFC to 4-[(4-fluorophenyl)-phenyl-methyl]hexa A solution of hydropyridine TFA salt (690 mg, 1.8 mmol) in MeOH (10 mL) was purified to give (S or R)-4-((4-fluorophenyl)(phenyl)methanone as a light yellow solid Group) hexahydropyridine (172 mg, 35%); MS (ESI): m/z = 270.1 [M+H] ⁺ ; and (R or S)-4-((4-fluorophenyl)(phenyl ) Methyl) hexahydropyridine. Dissolve (R or S)-4-((4-fluorophenyl)(phenyl)methyl)hexahydropyridine in EtOAc (15 mL) and use Na ₂ CO ₃ (5 mL, 30% aqueous solution) And washed with water (5 mL). The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum. The residue was lyophilized to give (R or S)-4-((4-fluorophenyl)(phenyl)methyl)hexahydropyridine (227 mg, 46%) as a pale yellow solid. MS (ESI): m/z = 270.1 [M+H] ⁺ .

Intermediate a) 4-[(4- Fluorophenyl )- Hydroxyl - Phenyl - methyl ] Hexahydropyridine -1- Tert-butyl formate To a solution of 4-bromofluorobenzene (2 g, 11.4 mmol) in THF (20 mL) cooled to -78°C was added n-butyllithium (5.81 mL, 14.51 mmol) dropwise, and the reaction mixture was stirred for 30 min . Then, a solution of tert-butyl 4-benzylhexahydropyridine-1-carboxylate (CAS RN 922504-27-6; 3 g, 10.37 mmol) in THF (15 mL) was added to the mixture, It was stirred at -78°C for 2 hours. Warm the mixture to room temperature and pour to saturated NH₄ Cl aqueous solution (50 mL) and extracted with EtOAc. The combined organic layer was passed through Na₂ SO₄ Dry, filter and concentrate in vacuo. The residue was purified by preparative HPLC (Gemini NX column) to obtain the title compound (1.18 g, 29%) as a colorless solid. MS: 312.1 [M-C₄ H₈ -H₂ O+H]⁺ .b) 4-[(4- Fluorophenyl )- Phenyl - Methylene ] Hexahydropyridine To a solution of 4-[(4-fluorophenyl)-hydroxy-phenyl-methyl]hexahydropyridine-1-carboxylic acid tert-butyl ester (0.7 g, 1.82 mmol) in DCM (10 mL) was added three Fluoroacetic acid (1.4 mL, 18.16 mmol), and the reaction was stirred at room temperature for 8 h. The mixture was concentrated in vacuo to give the crude title compound (0.3 g, 62%) as a light yellow solid. MS: 268.0 [M+H]⁺ . c) 4-[(4- Fluorophenyl )- Phenyl - methyl ] Hexahydropyridine trifluoroacetate A solution of 4-[(4-fluorophenyl)-phenyl-methylene]hexahydropyridine (1600 mg, 5.98 mmol) and Pd/C (300 mg, 5.98 mmol) in THF (100 mL) was added H₂ Stir at room temperature for 16 h under an atmosphere (760 mm Hg). The suspension was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC using TFA as an additive to obtain the title compound (700 mg, 29%) in the form of 2,2,2-trifluoroacetate salt as a white solid. MS (ESI): m/z = 270.1 [M+H]⁺ .

BB 105 (S or R)-4-((4- fluorophenyl )( p-tolyl ) methyl ) hexahydropyridine By SFC (Method: Column DAICEL Chiralpak AD 250 mm* 30mm, 5 µm , conditions 0.1% NH ₃ • H ₂ O IPA, start B 35, end B 35, gradient time (min) 4.9 min; 110 min, 100% B, maintenance time (min) 0; flow rate (mL/min) 60) separation 4 -[(4-fluorophenyl)-(p-tolyl)methyl]hexahydropyridine solution (870 mg, 3.07 mmol) to give ( R or S )-4-[(4-fluorophenyl)(p-toluene Yl)methyl]hexahydropyridine (253 mg, 28%; MS (ESI): m/z = 284.1 [M+H] ⁺ ) and ( S or R )-4-[(4-fluorophenyl)( P-tolyl)methyl]hexahydropyridine (356 mg, 40% yield; MS (ESI): m/z = 284.1 [M+H] ⁺ ).

Intermediate a) 4 - ((4- fluorophenyl) (hydroxy) (p-tolyl) methyl) piperidine-1-carboxylic acid tert-butyl ester at -78 deg.] C solution of 4-bromotoluene (1.70 g , 9.94 mmol) in THF (40 mL) was added a stirred solution of butyllithium (5.57 mL, 13.9 mmol). After stirring for 1 h, tert-butyl 4-(4-fluorobenzyl)hexahydropyridine-1-carboxylate (CAS RN 160296-40-2; 3.05 g, 9.94 mmol) was added to the Continue stirring at 78 °C for 1 h. The reaction was then warmed to 25°C and stirred for another 13 h. The reaction was quenched with NH ₄ Cl (saturated aqueous solution, 50 mL) and extracted with EtOAc (100 mL). The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to give the desired compound (2.85 g, 71%) as a light yellow oil. MS (ESI): m/z = 422.1 [M+Na] ⁺ . b) 4-[(4- fluorophenyl )-( p-tolyl ) methylene ] hexahydropyridine will 4-[(4-fluorophenyl)-hydroxy-(p-tolyl)methyl]hexahydropyridine A solution of tributyl -1-carboxylate (2.83 g, 7.08 mmol) and trifluoroacetic acid (11 mL, 142 mmol) in DCM (20 mL) was stirred at 25°C for 3 h. The reaction was concentrated under vacuum. The residue was purified by preparative HPLC (TFA as an additive) to obtain the title compound (1.36 mg, 67%) as a pale yellow semi-solid. MS (ESI): m/z = 282.1 [M+H] ⁺ . c) 4-[(4- fluorophenyl )-( p-tolyl ) methyl ] hexahydropyridine trifluoroacetate will 4-[(4-fluorophenyl)-(p-tolyl)methylene]hexa A solution of hydropyridine (1.36 g, 4.83 mmol) and Pd/C (300 mg) in DMF (50 mL) was stirred under H ₂ (2280 mm Hg) at 25°C for 16 h. The reaction solution was filtered through celite and concentrated under vacuum. The residue was purified by preparative HPLC (TFA as an additive) to obtain the desired compound (TFA salt, 870 mg, 45%) as a white semi-solid. MS (ESI): m/z = 284.1 [M+H] ⁺ .

BB106 (R or S)-4-((4-(2- fluoroethoxy ) phenyl )( phenyl ) methyl ) hexahydropyridine p-[[4-(2-fluoroethoxy)benzene ]-Phenyl-methyl]hexahydropyridine (800 mg, 2.55 mmol) in MeOH (5 mL) was purified and the enantiomers were separated by SFC to give (S or R) as a white solid -4-[[4-(2-fluoroethoxy)phenyl]-phenyl-methyl]hexahydropyridine (279 mg, 0.89 mmol, 35%); MS (ESI): m/z = 314.2 [ M+H] ⁺ ; and (R or S)-4-[[4-(2-fluoroethoxy)phenyl]-phenyl-methyl]hexahydropyridine (373 mg, 47%) as a white solid ). MS (ESI): m/z = 314.1 [M+H] ⁺ .

Intermediate 4-((4-(2- fluoroethoxy ) phenyl )( phenyl ) methyl ) hexahydropyridine The title compound is similar to intermediate 1-[(4-fluorophenyl)-phenyl- Methyl] hexahydropyrazine (CAS RN 27064-89-7), from 1-bromo-4-(2-fluoroethoxy)benzene (CAS RN 332-47-8) and 4-benzyl hexamethylene The preparation of the third butyl hydropyridine-1-carboxylate (CAS RN 922504-27-6) gave the title compound as a colorless oil. MS (ESI): m/z = 314.1 [M+H] ⁺ .

BB107 (S or R)-4-[(4- fluorophenyl )-(4 -methoxyphenyl ) methyl ] hexahydropyridine is separated by SFC to 4-[(4-fluorophenyl)-( 4-methoxyphenyl)methyl]hexahydropyridine (930 mg, 3.11 mmol) in MeOH (5 mL) was purified to give (S or R)-4-[( 4-fluorophenyl)-(4-methoxyphenyl)methyl]hexahydropyridine (277 mg, 0.93 mmol, 27%); MS (ESI): m/z = 300.1 [M+H] ⁺ ; And (R or S)-4-[(4-fluorophenyl)-(4-methoxyphenyl)methyl]hexahydropyridine (291 mg, 30%) as a light yellow semi-solid; MS (ESI ): m/z = 300.1 [M+H] ⁺ .

Intermediate 4-[(4- fluorophenyl )-(4 -methoxyphenyl ) methyl ] hexahydropyridine The title compound is similar to intermediate 1-[(4-fluorophenyl)-phenyl-methyl Group] hexahydropyrazine (CAS RN 27064-89-7), from 1-bromo-4-methoxy-benzene (CAS RN 104-92-7) and 4-benzyl hexahydropyridine-1- The preparation of tert-butyl formate (CAS RN 922504-27-6) began to yield the title compound as a colorless semi-solid. MS (ESI): m/z = 300.1 [M+H] ⁺ .

BB108 (R or S)-4-((4- fluorophenyl )( p-tolyl ) methyl ) hexahydropyridine By SFC (Method: Column DAICEL Chiralpak AD 250 mm* 30mm, 5 µm , condition 0.1 % NH ₃ • H ₂ O IPA, start B 35, end B 35, gradient time (min) 4.9 min; 110 min, 100% B, maintenance time (min) 0; flow rate (mL/min) 60) separation 4- [(4-fluorophenyl)-(p-tolyl)methyl]hexahydropyridine solution (870 mg, 3.07 mmol, BB105, intermediate c) to give ( R or S )-4-[(4-fluorobenzene Group) (p-tolyl) methyl] hexahydropyridine (253 mg, 28%); MS (ESI): m/z = 284.1 [M+H] ⁺ ; and ( S or R )-4-[(4 -Fluorophenyl)(p-tolyl)methyl]hexahydropyridine (356 mg, 40%). MS (ESI): m/z = 284.1 [M+H] ⁺ .

BB109 (S or R)-4-((3,4 -dimethoxyphenyl )(4- fluorophenyl ) methyl ) hexahydropyridine by SFC (Method: Column DAICEL Chiralpak AD (250 mm * 50 mm, 10 μm), condition 0.1% NH ₃ •H ₂ O MeOH, start B 25, end B 25, gradient time (min) 5.5 min: 900 min, 100% B, maintenance time (min) 0, flow rate ( mL/min) 50 g/min) to separate 4-((3,4-dimethoxyphenyl)(4-fluorophenyl)methyl)hexahydropyridine (900 mg) to give ( S Or R )-4-((3,4-dimethoxyphenyl)(4-fluorophenyl)methyl)hexahydropyridine (278 mg, 29%d). MS (ESI): m/z = 330.3 [M+H] ⁺ and ( R or S )-4-((3,4-dimethoxyphenyl)(4-fluorophenyl)methyl)hexahydro Pyridine (426 mg, 44%; MS (ESI): m/z = 330.1 [M+H] ⁺ ).

Intermediate a) 4-((3,4 -Dimethoxyphenyl )(4- fluorophenyl )( hydroxy ) methyl ) hexahydropyridine- 1- carboxylic acid tert-butyl ester at -78°C A solution of 4-bromoveratrole (CAS RN 2859-78-1; 1.27 g, 5.86 mmol) in THF (30 mL) was added dropwise with butyllithium (3.28 mL, 8.2 mmol) and stirred. Continue stirring at -78 °C for 1 h. Then 4-(4-fluorobenzyl)hexahydropyridine-1-carboxylic acid tert-butyl ester (CAS RN 160296-40-2; 1.80 g, 5.86 mmol) was added, and the mixture was stirred at -78°C 5 h. The mixture was poured into brine (50 mL) and extracted twice with EtOAc (30 mL each time). The combined organic layer was concentrated in vacuo to give the desired compound (2.4 g, 91%) as a colorless oil. MS (ESI): m/z = 468.4 [M+Na] ⁺ . b) 4-((3,4 -dimethoxyphenyl )(4- fluorophenyl ) methylene ) hexahydropyridine trifluoroacetate will 4-((3,4-dimethoxyphenyl )(4-fluorophenyl)(hydroxy)methyl)hexahydropyridine-1-carboxylic acid tert-butyl ester (2.4 g, 5.4 mmol) and trifluoroacetic acid (4.15 mL, 53.87 mmol) in DCM (20 mL) The mixture in was stirred at 25°C for 4 h. The reaction mixture was concentrated in vacuo to give 4-((3,4-dimethoxyphenyl)(4-fluorophenyl)methylene)hexahydropyridine (TFA salt, 1.7 g as a brown oil , 96%). MS (ESI): m/z = 328.3 [M+H] ⁺ . c) 4-((3,4 -dimethoxyphenyl )(4- fluorophenyl ) methyl ) hexahydropyridine will 4-((3,4-dimethoxyphenyl)(4-fluoro Phenyl)methylene)hexahydropyridine (1.7 g, 5.2 mmol, BB109, intermediate b) and a mixture of Pd/C (276 mg, 0.260 mmol) in THF (10 mL) in H ₂ (760 mm Hg ) Under stirring at 25 ° C for 16 h. The mixture was filtered and concentrated in vacuo to obtain a residue, which was purified by preparative HPLC (TFA conditions) to give 4-((3,4-dimethoxyphenyl)(4- Fluorophenyl) methyl) hexahydropyridine (900 mg, 52%). MS (ESI): m/z = 330.3 [M+H] ⁺ .

BB110 (R or S)-4-((3,4 -dimethoxyphenyl ) ( phenyl ) methyl ) hexahydropyridine separation of 4-[(3,4-dimethoxybenzene by SFC )-Phenyl-methyl] hexahydropyridine (900 mg, 2.89 mmol) in MeOH (5 mL) was purified to give (S or R)-(3,4-dimethoxy) as a white solid Phenyl)-phenyl-methyl]hexahydropyridine (326 mg, 36%); MS (ESI): m/z = 312.3 [M+H] ⁺ ; and (R or S)- as a white solid (3,4-dimethoxyphenyl)-phenyl-methyl]hexahydropyridine (222 mg, 24%); MS (ESI): m/z = 312.3 [M+H] ⁺ .

Intermediate 4-[(3,4 -dimethoxyphenyl ) -phenyl - methyl ] hexahydropyridine The title compound is similar to intermediate 1-[(4-fluorophenyl)-phenyl-methyl ] Hexahydropyrazine (CAS RN 27064-89-7), from 4-bromo-1,2-dimethoxy-benzene (CAS RN 2859-78-1) and 4-benzyl hexahydropyridine- The third butyl 1-carboxylate (CAS RN 922504-27-6) was prepared to give the title compound as a white solid. MS (ESI): m/z = 312.3 [M+H] ⁺ .

BB111 (R or S)-4-((4- fluorophenyl )( phenyl ) methyl ) hexahydropyridine is separated by SFC to 4-[(4-fluorophenyl)-phenyl-methyl]hexa A solution of hydropyridine TFA salt (690 mg, 1.8 mmol) in MeOH (10 mL) was purified to give (S or R)-4-((4-fluorophenyl)(phenyl)methanone as a light yellow solid Base) hexahydropyridine (172 mg, 35%). MS (ESI): m/z = 270.1 [M+H] ⁺ ; and (R or S)-4-((4-fluorophenyl)(phenyl)methyl)hexahydropyridine. Dissolve (R or S)-4-((4-fluorophenyl)(phenyl)methyl)hexahydropyridine in EtOAc (15 mL) and use aqueous Na ₂ CO ₃ (5 mL, 30%) And washed with water (5 mL). The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum. The residue was lyophilized to give (R or S)-4-((4-fluorophenyl)(phenyl)methyl)hexahydropyridine (227 mg, 0.84 mmol, 46%) as a light yellow solid; MS (ESI): m/z = 270.1 [M+H] ⁺ .

BB112 (S or R)-4-( phenyl ( m-tolyl ) methyl ) hexahydropyridine Separation of 4-(phenyl(m-tolyl)methyl) hexahydropyridine (730 mg, 2.75 mmol) by SFC ) In MeOH (5 mL) was purified to give (S or R)-4-(phenyl(m-tolyl)methyl)hexahydropyridine (221 mg, 0.83 mmol, 30%) as a yellow semi-solid ). MS (ESI): m/z = 266.2 [M+H] ⁺ ; and (R or S)-4-(phenyl(m-tolyl)methyl)hexahydropyridine (228 mg, 31) as a yellow semi-solid %). MS (ESI): m/z = 266.2 [M+H] ⁺ .

Intermediate 4-( phenyl ( m-tolyl ) methyl ) hexahydropyridine The title compound is similar to intermediate 1-[(4-fluorophenyl)-phenyl-methyl]hexahydropyrazine (CAS RN 27064 -89-7), from 1-bromo-3-methyl-benzene (CAS RN 591-17-3) and tert-butyl 4-benzylhexahydropyridine-1-carboxylate (CAS RN 922504- 27-6) To begin the preparation, the title compound is obtained as a light yellow solid. MS (ESI): m/z = 266.1 [M+H] ⁺ .

BB113 (S or R)-4-((4-(2- fluoroethoxy ) phenyl )( phenyl ) methyl ) hexahydropyridine p-[[4-(2-fluoroethoxy)benzene ]-Phenyl-methyl] hexahydropyridine (BB106, intermediate; 800 mg, 2.55 mmol) in MeOH (5 mL) was purified, and the mirror image isomers were separated by SFC separation to obtain (S or R)-4-[[4-(2-fluoroethoxy)phenyl]-phenyl-methyl]hexahydropyridine (279 mg, 35%) as a white solid, MS (ESI): m/z = 314.2 [M+H] ⁺ ; and (R or S)-4-[(S)-[4-(2-fluoroethoxy)phenyl]-phenyl-methyl as a white solid ] Hexahydropyridine (373 mg, 47%); MS (ESI): m/z = 314.1 [M+H] ⁺ .

BB114 (R or S)-4-( phenyl ( m-tolyl ) methyl ) hexahydropyridine p-(phenyl(m-tolyl)methyl)hexahydropyridine (BB112, intermediate, 730 mg, 2.75 mmol) in MeOH (5 mL) was purified, and the mirror image isomers were separated using SFC to give (S or R)-4-(phenyl(m-tolyl)methyl)hexahydro as a yellow semi-solid Pyridine (221 mg, 30%); MS (ESI): m/z = 266.2 [M+H] ⁺ ; and (R or S)-4-(phenyl(m-tolyl)methyl) as a yellow semi-solid ) Hexahydropyridine (228 mg, 31%). MS (ESI): m/z = 266.2 [M+H] ⁺ .

BB115 (S or R)-4-( phenyl ( p-tolyl ) methyl ) hexahydropyridine p-(phenyl(p-tolyl)methyl)hexahydropyridine (720 mg, 2.71 mmol) in MeOH ( The solution in 5 mL) was purified and the mirror image isomers were separated using SFC to give ((S or R)-4-(phenyl(p-tolyl)methyl)hexahydropyridine (277 mg, 35%); MS (ESI): m/z = 266.2 [M+H] ⁺ ; and (R or S)-4-(phenyl(p-tolyl)methyl)hexahydropyridine (313 mg, 43%); MS (ESI): m/z = 266.2 [M+H] ⁺ .

Intermediate 4-( phenyl ( p-tolyl ) methyl ) hexahydropyridine The title compound is similar to intermediate 1-[(4-fluorophenyl)-phenyl-methyl]hexahydropyrazine (CAS RN 27064 -89-7), from 1-bromo-4-methyl-benzene (CAS RN 106-38-7) and tert-butyl 4-benzylhexahydropyridine-1-carboxylate (CAS RN 922504- 27-6) Start preparation to obtain the title compound as a white solid, MS (ESI): m/z = 266.2 [M+H] ⁺ .

BB116 (R or S)-4-( phenyl ( p-tolyl ) methyl ) hexahydropyridine p-(phenyl(p-tolyl)methyl)hexahydropyridine (BB117, intermediate, 720 mg, 2.71 The solution of mmol) in MeOH (5 mL) was purified and the mirror image isomer was separated using SFC to give ((S or R)-4-(phenyl(p-tolyl)methyl)hexahydro as an off-white solid Pyridine (277 mg, 1.04 mmol, 35%); MS (ESI): m/z = 266.2 [M+H] ⁺ ; and (R or S)-4-(phenyl (p-tolyl)) as an off-white solid Methyl) hexahydropyridine (313 mg, 1.18 mmol, 43%); MS (ESI): m/z = 266.2 [M+H] ⁺ .

BB117 3- Diphenylmethylazetidine Combine 3- (diphenylmethylene)azetidine (800 mg, 3.62 mmol) and Pd/C (1923 mg) in THF (20 mL) The solution was stirred at 25°C for 5 h under H ₂ atmosphere (760 mm Hg). The solution was filtered and concentrated in vacuo to obtain a residue, which was purified by preparative HPLC (TFA condition) to obtain 3-benzylazetidine (315 mg, 37%) as a white solid ). MS (ESI): m/z = 224.1 [M+H] ⁺ .

Intermediate a) 3-[ Methoxy ( methyl ) aminecarboxamide ] azetidine- 1- carboxylic acid tert-butyl ester 1-boc-azetidine-3-carboxylic acid (CAS RN 142253-55-2; 50 g, 248 mmol), triethylamine (69.3 mL, 497 mmol), 1-hydroxybenzotriazole (33.5 g, 248 mmol) and EDCl (47.6 g, 248 mmol) and O , A mixture of N -dimethylhydroxylamine hydrochloride (24.24 g, 248.5 mmol) in DMF (1000 mL) was stirred at 25°C for 16 h. The mixture was concentrated in vacuo to give a residue, which was neutralized to pH = 7 by HCl (1 M) and extracted three times with EtOAc (200 mL each time). The combined organic layer was washed twice with 200 mL of NaHCO ₃ aqueous solution, dried over Na ₂ SO ₄ and concentrated in vacuo to give 3-[methoxy(methyl)aminemethanyl] nitrogen as a colorless oil Heterocyclobutane-1-carboxylic acid tert-butyl ester (55 g, 72%). MS (ESI): m/z = 189.1 [MC ₄ H ₈ +H] ⁺ . b) 3- Benzoylazetidine- 1- carboxylic acid tert-butyl ester at 0°C to 3-[methoxy(methyl)aminemethylacetoyl]azetidine-1- A solution of tert-butyl formate (55 g, 225 mmol) in THF (600 mL) was added phenylmagnesium bromide (82 mL, 248 mmol) and stirred, and then the solution was stirred at 0°C for 3 h. The solution was poured into saturated aqueous NH ₄ Cl (300 mL) and extracted twice with EtOAc (150 mL each time). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to obtain a residue, which was purified by column chromatography (petroleum ether: EtOAc 10: 1) to give the desired as a light yellow solid Compound (28 g, 46%). MS (ESI): m/z = 206.1 [MC ₄ H ₈ +H] ⁺ . c) 3-( Hydroxydiphenylmethyl ) azetidine- 1- carboxylic acid tert-butyl ester, phenylmagnesium bromide (3.06 mL, 9.18 mmol) and 3-benzyl azetidine A solution of alkane-1-carboxylic acid tert-butyl ester (2.0 g, 7.65 mmol) in THF (20 mL) was stirred at 0 °C for 2 h. The solution was quenched by the addition of saturated aqueous NH ₄ Cl (50 mL) and extracted twice with EtOAc (20 mL each time). The combined organic layer was concentrated in vacuo to give a residue, which was purified by flash column chromatography (PE: EtOAc 5: 1) to give the desired compound as a white solid (1.03 g, 39%). MS (ESI): m/z = 362.2 [M+Na] ⁺ . d) 3-( diphenylmethylene ) azetidine trifluoroacetate, 3-(hydroxydiphenylmethyl)azetidine-1-carboxylic acid tert-butyl ester (1.00 g, 2.95 mmol) and TFA (2.27 mL, 29.5 mmol) in DCM (15 mL) were stirred at 25 °C for 4 h. The solution was concentrated in vacuo to provide the title compound (TFA salt, 650 mg, 99%) as a brown oil. MS (ESI): m/z = 222.1 [M+H] ⁺ .

BB118 (S or R)-4-((3,4 -dimethoxyphenyl )( phenyl ) methyl ) hexahydropyridine p-[[3,4-dimethoxyphenyl)-benzene -Methyl] hexahydropyridine (BB110, intermediate; 900 mg, 2.89 mmol) in MeOH (5 mL) was purified, and the enantiomers were separated using SFC to give (S or R as a white solid )-(3,4-dimethoxyphenyl)-phenyl-methyl]hexahydropyridine (326 mg, 1.05 mmol, 36%); MS (ESI): m/z = 312.3 [M+H] ⁺ ; and (R or S)-(3,4-dimethoxyphenyl)-phenyl-methyl]hexahydropyridine (222 mg, 0.71 mmol, 24%) as a white solid. MS (ESI): m/z = 312.3 [M+H] ⁺ .

BB119 (R or S)-4-((3,4 -dimethoxyphenyl )(4- fluorophenyl ) methyl ) hexahydropyridine by SFC (Method: Column DAICEL Chiralpak AD (250 mm * 50 mm, 10 μm), condition 0.1% NH ₃ •H ₂ O MeOH, start B 25, end B 25, gradient time (min) 5.5 min: 900 min, 100% B, maintenance time (min) 0, flow rate ( mL/min) 50 g/min) to isolate 4-((3,4-dimethoxyphenyl)(4-fluorophenyl)methyl)hexahydropyridine (BB109, intermediate c; 900 mg) to give ( S or R )-4-((3,4-Dimethoxyphenyl)(4-fluorophenyl)methyl)hexahydropyridine (278 mg, 29%; MS (ESI): m/z = 330.3 [M+H] ⁺ ) and ( R or S )-4-((3,4-dimethoxyphenyl)(4-fluorophenyl)methyl)hexahydropyridine (426 mg , 44%; MS (ESI): m/z = 330.1 [M+H] ⁺ ).

BB120 (R or S)-4-[(4- fluorophenyl )-(4 -methoxyphenyl ) methyl ] hexahydropyridine 4-[(4-fluorophenyl)-(4-methoxy Phenyl)methyl]hexahydropyridine (BB107, intermediate; 930 mg, 3.11 mmol) in MeOH (5 mL) for purification, and using SFC to separate the enantiomers, to give a pale yellow semi-solid (S or R)-4-[(4-fluorophenyl)-(4-methoxyphenyl)methyl]hexahydropyridine (277 mg, 27%); MS (ESI): m/z = 300.1 [M+H] ⁺ ; and (R or S)-4-[(4-fluorophenyl)-(4-methoxyphenyl)methyl]hexahydropyridine (291 mg, 30%); MS (ESI): m/z = 300.1 [M+H] ⁺ .

BB121 (R or S)-4-((4-(2- fluoroethoxy ) phenyl )(4- fluorophenyl ) methyl ) hexahydropyridine 4-([4-(2-fluoroethoxy Group) phenyl]-(4-fluorophenyl)methyl] hexahydropyridine (700 mg, 2.11 mmol) in MeOH (5 mL) was purified, and the enantiomers were separated using SFC to give colorless Oily (R or S)-4-[[4-(2-fluoroethoxy)phenyl]-(4-fluorophenyl)methyl]hexahydropyridine (203 mg, 29%); MS (ESI): m/z = 332.2 [M+H] ⁺ ; and (S or R)-4-[[4-(2-fluoroethoxy)phenyl]-(4- Fluorophenyl)methyl]hexahydropyridine (160 mg, 23%); MS (ESI): m/z = 332.2 [M+H] ⁺ .

Intermediate 4-[[4-(2- fluoroethoxy ) phenyl ]-(4- fluorophenyl ) methyl ] hexahydropyridine The title compound is similar to intermediate 1-[(4-fluorophenyl) -Phenyl-methyl]hexahydropyrazine (CAS RN 27064-89-7), from 1-bromo-4-(2-fluoroethoxy)benzene (CAS RN 332-47-8) and 4-( 4-fluorobenzyl) hexahydropyridine-1-carboxylic acid tert-butyl ester (CAS RN 160296-40-2) was prepared to obtain the title compound as a colorless oil. MS (ESI): m/z = 332.1 [M+H] ⁺ .

BB122 (R or S)-4-((3-(2- fluoroethoxy ) phenyl )( phenyl ) methyl ) hexahydropyridine p-[[3-(2-fluoroethoxy)benzene ]-Phenyl-methyl] hexahydropyridine (BB103, intermediate; 800 mg, 2.55 mmol) in MeOH (5 mL) was purified, and the enantiomers were separated using SFC to give a white solid (S or R)-4-((3-(2-fluoroethoxy)phenyl)(phenyl)methyl)hexahydropyridine (214 mg, 27%); MS (ESI): m/z = 314.1 [M+H] ⁺ ; and (R or S)-4-((3-(2-fluoroethoxy)phenyl)(phenyl)methyl)hexahydropyridine (305 mg, as a white solid 38%). MS (ESI): m/z = 314.1 [M+H] ⁺ .

BB123 (S or R)-4-((4-(2- fluoroethoxy ) phenyl )(4- fluorophenyl ) methyl ) hexahydropyridine 4-([4-(2-fluoroethoxy Group) phenyl]-(4-fluorophenyl)methyl] hexahydropyridine (BB121, intermediate; 700 mg, 2.11 mmol) in MeOH (5 mL) was purified, and the mirror image was separated by SFC Structure to give (R or S)-4-[[4-(2-fluoroethoxy)phenyl]-(4-fluorophenyl)methyl]hexahydropyridine (203 mg) as a colorless oil , 29%); MS (ESI): m/z = 332.2 [M+H] ⁺ ; and (S or R)-4-[[4-(2-fluoroethoxy)benzene as a colorless oil Group]-(4-fluorophenyl)methyl]hexahydropyridine (160 mg, 23%). MS (ESI): m/z = 332.2 [M+H] ⁺ .

BB124 (2-(3-( phenyl ( hexahydropyridin- 4 -yl ) methyl ) phenoxy ) ethyl ) carbamic acid tert-butyl ester to 4-((3-(2-(( Tributoxycarbonyl)amino)ethoxy)phenyl)(phenyl)methylene)hexahydropyridine-1-carboxylic acid benzyl ester (60 mg, 111 μmol), methanol (3 mL) and AcOH ( 60 μL) of the mixture was filled with Pt-Pd/C (60 mg, 2.5%+2.5%, 63% H ₂ O) and placed under a hydrogen atmosphere (50 bar). The mixture was shaken at 50°C for 2 h, diluted with EtOAc and filtered. The filtrate was washed with KHCO ₃ and the organic layer was dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to give the crude title compound (33 mg, 68%) as a white foam, which was used in the next reaction step without further purification. MS (ESI): m/z = 411.3 [M+H] ⁺ .

Intermediate a) (Z)-4-( phenyl (2 -toluenesulfonylhydrazide ) methyl ) hexahydropyridine- 1- carboxylic acid benzyl ester 4-toluenesulfonylhydrazine (1.54 g, 8.29 mmol , CAS RN 1576-35-8) and tert-butyl 4-benzylhexahydropyridine-1-carboxylate (2 g, 6.91 mmol, CAS RN 922504-27-6) in 1,4-dioxane The solution in alkane (150 mL) was stirred at 100°C for 16 h. Add EtOAc and water. The layers were separated, and the organic layer was dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography (25 g silica gel; EtOAc gradient (0-30%) in n-heptane) to give the title compound (3.55 g) as a light brown oil , 82%). MS (ESI): m/z = 492.2 [M+H] ⁺ . b) 4-((3-(2-(( Third-butoxycarbonyl ) amino ) ethoxy ) phenyl )( phenyl ) methylene ) hexahydropyridine- 1- carboxylic acid benzyl ester ( Z)-4-(phenyl(2-toluenesulfonylhydrazide)methyl)hexahydropyridine-1-carboxylic acid benzyl ester (1 g mg, 2.03 mmol), bis(triphenylphosphine) chloride Palladium(II) (143 mg, 203 µmol), lithium tert-butoxide (246 mg, 3.05 mmol) and N-boc-2-(3-bromophenoxy)ethylamine (CAS RN 1098107-26-6; A mixture of 772 mg, 2.44 µmol) in 1,4-dioxane (65 mL) was stirred at 80°C for 12 h. Add EtOAc and water. The layers were separated, and the organic layer was dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography (80 g silica gel; EtOAc gradient in n-heptane 0%-30%) to give the title compound (280 mg, twenty two%). MS (ESI): m/z = 443.2 [M-Boc+H] ⁺ .

BB125 5- chloro -2-( hexahydropyridin- 4 -yl ) isoindoline hydrochloride This compound is similar to BB52, from 4-(5-chloroisoindolin-2-yl)hexahydropyridine- 1-Butyl formate is obtained as the desired compound as a light green solid. MS (ESI): m/z = 237.2 [M+H] ⁺ .

Intermediate 4-(5 -chloroisoindolin- 2- yl ) hexahydropyridine- 1- carboxylic acid tert-butyl ester This compound is similar to BB148 intermediate, from 5-chloroisoindolin hydrochloride ( CAS RN 912999-79-2) to obtain the desired compound as a light brown solid. MS (ESI): m/z = 337.3 [M+H] ⁺ .

BB126 (4aS, 8aS) - hexahydro--2H- pyrido [4,3-b] [1,4] oxazin -3 (4H) - one hydrochloride (4aS, 8aS) -3- oxo Hexahydro-2H-pyrido[4,3-b][1,4]oxazine-6(5H)-carboxylic acid tert-butyl ester (330 mg, 1.29 mmol) in 2 M hydrochloric acid (in ether) The white suspension (6.44 ml, 12.9 mmol) was stirred at room temperature for 22 hours. The colorless suspension was filtered and washed with diethyl ether to obtain the desired product (0.172 g; 69.3%) as a colorless solid. MS (ESI): m/z = 157.0990 [M+H] ⁺ .

Intermediates a) (4aS, 8aS) -3- oxo-hexahydro -2H- pyrido [4,3-b] [1,4] oxazine -6 (5H) - carboxylate third-butyl ( 3S,4S)-3-(2-chloroacetamido)-4-hydroxyhexahydropyridine-1-carboxylic acid tert-butyl ester (436 mg, 1.49 mmol) in DCM (7 ml) A solution of potassium tert-butoxide (668 mg, 5.96 mmol) in 2-propanol (18 ml) was added dropwise. The ice bath was removed, and the mixture was stirred at room temperature for 24 hours while obtaining a white suspension. The mixture was evaporated. The residue was dissolved in ethyl acetate and water, and the layers were separated. The aqueous layer was extracted twice with ethyl acetate. The organic layer was dried over MgSO ₄ , filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography using a MPLC system on a 40 g column using a gradient of DCM:MeOH (100:0 to 90:10) to obtain the desired compound (330 mg; colorless foam). 86.5% yield). MS (ESI): m/z = 201.1 [M-C4H8+H] ⁺ . b) (3S, 4S) -3- (2- chloro-acetylglucosamine) -4-hydroxy-piperidine-1-carboxylic acid butyl ester To a third (3S, 4S) -3- amino-4-hydroxy Tert-butyl hexahydropyridine-1-carboxylate (500 mg, 2.31 mmol, CAS RN 1312812-78-4) and sodium acetate trihydrate (629 mg, 4.62 mmol) in acetone (4 ml) and water (300 µl) of the ice-cold suspension was added dropwise a solution of 2-chloroacetamide chloride (261 mg, 184 µl, 2.31 mmol) in acetone (500 µl). The mixture was stirred at room temperature for 3 hours, after which silicone glue was added. The suspension is evaporated. The compound was purified by silica gel chromatography using a MPLC (ISCO) system using a gradient of n-heptane:ethyl acetate (100:0 to 0:100) on a 12 g column to obtain a colorless foam. The desired compound (436 mg; 64.4%). MS (ESI): m/z = 291.3 [MH] ^- .

BB127 4-[1-[4-( trifluoromethyl ) phenyl ] ethyl ] hexahydropyridinecarboxylate will 4-[1-[4-(trifluoromethyl)phenyl]ethyl]hexahydro A solution of tert-butyl pyridine-1-carboxylate (1500.0 mg, 4.2 mmol) in HCl in dioxane (50.0 mL, 200 mmol) was stirred at 20°C for 2 h. The mixture was concentrated and the residue was purified by preparative HPLC (FA) and lyophilized to give the desired compound (838.4 mg, 77.1%) as a pale yellow oil. MS (ESI): m/z = 258.1 [M+H] ⁺ .

Intermediate a) 4-[1-[4-( Trifluoromethyl ) phenyl ] vinyl ] hexahydropyridine- 1- carboxylic acid tert-butyl ester at 0°C to methyltriphenylphosphonium bromide ( 499.8 mg, 1.4 mmol, CAS RN 1779-49-3) in THF (10 mL) was added potassium tert-butoxide (235.5 mg, 2.1 mmol) in portions, and the mixture was stirred at 0°C for 30 min. 4-[4-(Trifluoromethyl)benzyl]hexahydropyridine-1-carboxylic acid tert-butyl ester (500.0 mg, 1.4 mmol, CAS RN 725229- 27-6), and the mixture was warmed to 20°C and stirred at room temperature for 12 h. The mixture was poured into saturated aqueous NH ₄ Cl (50 mL) and extracted twice with EtOAc (20 mL each time). The layers were separated, the organic phase was washed with brine, dried over Na ₂ SO ₄ and filtered. The filtrate was purified by a silica gel column (PE: EtOAc = 20: 1) to obtain the desired compound (200 mg, 40.2%) as a pale yellow oil. MS: MS (ESI): m/z = 300.0 [MC ₄ H ₈ +H] ⁺ . b) 4-[1-[4-( trifluoromethyl ) phenyl ] ethyl ] hexahydropyridine- 1- carboxylic acid tert-butyl ester to 4-[1-[4-(trifluoromethyl)benzene Base] vinyl] hexahydropyridine-1-carboxylic acid tert-butyl ester (2.0 g, 5.63 mmol) in EtOAc (100 mL) was added Pd/C (1.0 g, 5.63 mmol), and the mixture was hydrogenated Stir at 20°C for 12 h under an atmosphere. The mixture was filtered and the filtrate was concentrated to give the crude product (1.8 g, 89.5%) as a colorless oil, which was used in the next step without further purification. MS (ESI): m/z = 302.2 [MC ₄ H ₈ +H] ⁺ .

BB128 3-( hexahydropyridin- 4 -yl )-5-( trifluoromethyl ) pyridine dihydrochloride in a 25 mL tube, place 4-(5-(trifluoromethyl)pyridin-3-yl)hexa The third butyl hydropyridine-1-carboxylate (110 mg, 333 µmol) was dissolved in DCM (1 mL), and 2 M HCl (2 mL, 4 mmol) in ether was added. The reaction was stirred at room temperature for 6 h. The solvent was removed in vacuo to obtain 100 mg (99%) of crude product as a white foam. It was used without further purification. MS (ESI): m/z = 231.1 [M+H] ⁺ .

Intermediate : a) 4-(5-( Trifluoromethyl ) pyridin- 3 -yl ) hexahydropyridine- 1- carboxylic acid tert-butyl ester in a 25 mL three-necked dry flask, and zinc powder (172 mg, 2.63 mmol) was combined with 1 mL DMA (on molecular sieve) to obtain a gray suspension. Stir the mixture at room temperature while adding 7:5 of chlorotrimethylsilane (32 ul) and 1,2-dibromoethane (22 ul) at a rate to maintain the temperature below 65°C (slightly exothermic) Solution of v/v mixture in DMA (1 mL). The resulting slurry was stirred for 20 minutes. A solution of tert-butyl 4-iodohexahydropyridine-1-carboxylate (688 mg, 2.21 mmol) in 2 mL DMA was slowly added to the mixture. Then, the resulting reaction mixture was stirred at room temperature for 30 minutes. Without stirring, the reaction was allowed to stand for 15 min for decantation. In a 25 mL three-necked flask, combine 3-bromo-5-(trifluoromethyl)pyridine (250 mg, 1.11 mmol) with 1.5 mL DMA to obtain a colorless solution, and add copper (I) iodide (21.1 mg, 111 µmol) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium(II) complex with dichloromethane (45.2 mg, 55.3 µmol). The reaction mixture was degassed with argon, freshly prepared zinc reagent solution was added, degassed again with argon, and the reaction mixture was stirred at 80°C overnight. The reaction mixture was quenched with 10 mL of saturated aqueous NH ₄ Cl solution and extracted twice with EtOAc (40 mL each time). The organic layer was washed with brine. The organic layers were combined, dried over MgSO ₄ and concentrated in vacuo. Purification by SiO ₂ flash chromatography using 0% to 80% n-heptane/EtOAc in 35 min gave the desired product (112 mg, 31%) as a light yellow oil. MS (ESI): m/z = 331.2 [M+H] ⁺ .

BB129 4-( difluoro (4-( trifluoromethyl ) phenyl ) methyl ) hexahydropyridine hydrochloride will 4-(difluoro(4-(trifluoromethyl)phenyl)methyl)hexahydro Pyridine-1-carboxylic acid tert-butyl ester (0.338 g, 891 µmol) was dissolved in DCM (1 mL), and 2 M HCl (4.45 mL, 8.91 mmol) in ether was added. The reaction was stirred at room temperature for 16 h. The solvent was removed in vacuo to obtain 246 mg (82%) of crude product as an off-white solid. It was used without further purification. MS (ESI): m/z = 280.11 [M+H] ⁺ .

Intermediate : a) 4-(4-( trifluoromethyl ) benzyl ) hexahydropyridine- 1- carboxylic acid tert-butyl ester at 0°C under argon to hexahydropyridin-4-yl(4 -(Trifluoromethyl)phenyl)methanone hydrochloride (0.500 g, 1.7 mmol), triethylamine (345 mg, 475 µl, 3.4 mmol) and DMAP (62.4 mg, 511 µmol) in acetonitrile (10 mL ) Was added Boc ₂ O (446 mg, 2.04 mmol). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into 15 mL saturated NaHCO ₃ and extracted twice with EtOAc (25 mL each time). The organic layers were combined, washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude material was triturated with n-heptane to produce the desired product (354 mg, 58%) as an off-white solid, which was used directly in the next step. MS (ESI): m/z = 302.1 [MC ₄ H ₈ +H] ⁺ . b) 4-( Difluoro (4-( trifluoromethyl ) phenyl ) methyl ) hexahydropyridine- 1- carboxylic acid tert-butyl ester to 4-(4-(trifluoromethyl)benzyl group ) A solution of tert-butyl hexahydropyridine-1-carboxylate (0.350 g, 979 µmol) in DCM (3 mL) was added DAST (5.53 g, 34.3 mmol). The reaction mixture was stirred at 45°C for three days. The reaction mixture was poured into 15 mL H ₂ O and ice, and extracted twice with DCM (20 mL each time). The organic layers were combined, washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 20 g, 0% to 20% EtOAc in n-heptane) to provide the desired compound as a yellow oil (341 mg, 92%). MS (ESI): m/z = 379.1 [M+H] ⁺ .

BB130 3 -methoxy- 5-( hexahydropyridin- 4 -yl ) pyridine dihydrochloride in a 25 mL tube, place 4-(5-methoxypyridin-3-yl)hexahydropyridine-1- The third butyl formate (150 mg, 513 µmol) was dissolved in DCM (1 mL), and 2 M HCl (2.57 mL, 5.13 mmol) in ether was added. The reaction was stirred at room temperature for 3 h. The solvent was removed in vacuo to obtain 136 mg (100%) of crude product as a pale yellow foam. It was used without further purification. MS (ESI): m/z = 193.1 [M+H] ⁺ .

Intermediate: 4-(5 -Methoxypyridin- 3 -yl ) hexahydropyridine- 1- carboxylic acid tert-butyl ester In a 25 mL three-necked dry flask, mix zinc powder (232 mg, 3.54 mmol) with 1 The mL DMA was combined (on the molecular sieve) to obtain a gray suspension. Stir the mixture at room temperature while adding 7:5 of chlorotrimethylsilane (32 ul) and 1,2-dibromoethane (22 ul) at a rate to maintain the temperature below 65°C (slightly exothermic) Solution of v/v mixture in DMA (1 mL). The resulting slurry was stirred for 20 minutes. A solution of tert-butyl 4-iodohexahydropyridine-1-carboxylate (927 mg, 2.98 mmol) in 2 mL DMA was slowly added to the mixture. Then, the resulting reaction mixture was stirred at room temperature for 30 minutes. Without stirring, the reaction was allowed to stand for 15 min for decantation. In a 25 mL three-necked flask, combine 3-bromo-5-methoxypyridine (280 mg, 1.49 mmol) with 1.5 mL DMA to obtain a colorless solution, add copper(I) iodide (28.4 mg, 149 µmol) And [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (60.8 mg, 74.5 µmol). The reaction mixture was degassed with argon, freshly prepared zinc reagent solution was added, degassed again with argon, and the reaction mixture was stirred at 80°C for 6 hours. The reaction mixture was quenched with 10 mL saturated NH ₄ Cl, and extracted twice with EtOAc (40 mL each time). The organic layer was washed with brine. The organic layers were combined, dried over MgSO ₄ and concentrated in vacuo. Purification by SiO ₂ flash chromatography using 0% to 100% n-heptane/EtOAc in 35 min gave the desired product (150 mg, 34.5%) as a light yellow oil. MS (ESI): m/z = 293.2 [M+H] ⁺ .

BB131 4-((4- chlorophenyl ) difluoromethyl ) hexahydropyridine hydrochloride will 4-(difluoro(4-(trifluoromethyl)phenyl)methyl)hexahydropyridine-1-carboxylic acid The third butyl ester (440 mg, 1.27 mmol) was dissolved in DCM (2 mL), and 2 M HCl (6.36 mL, 12.7 mmol) in ether was added. The reaction was stirred at room temperature for 64 hours. The solvent was removed in vacuo to obtain 323 mg (90%) of crude product as an off-white solid. It was used without further purification. MS (ESI): m/z = 246.1 [M+H] ⁺ .

Intermediate 4-( difluoro (4-( trifluoromethyl ) phenyl ) methyl ) hexahydropyridine- 1- carboxylic acid tert-butyl ester to 4-(4-chlorobenzyl)hexahydropyridine- A solution of tert-butyl 1-carboxylate (0.500 g, 1.54 mmol) in DCM (3 mL) was added DAST (8.71 g, 54 mmol). The reaction mixture was stirred at 45°C for eight days. The reaction mixture was poured into 15 mL H ₂ O and ice, and extracted twice with DCM (20 mL each time). The organic layers were combined, washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 20 g, 0% to 20% EtOAc in n-heptane) to provide the desired product (440 mg, 82%) as a yellow oil. MS (ESI): m/z = 345.1 [M+H] ⁺ .

BB132 2-( hexahydropyridin- 4 -yl )-5-( trifluoromethoxy ) pyridine dihydrochloride in a 25 mL tube, place 4-(5-(trifluoromethoxy)pyridine-2- Yl) hexahydropyridine-1-carboxylic acid tert-butyl ester (380 mg, 1.1 mmol) was dissolved in DCM (2 mL), and 2 M HCl (3.29 mL, 6.58 mmol) in diethyl ether was added. The reaction was stirred at room temperature for 4 h. The solvent was removed in vacuo to obtain the crude product as a pale yellow foam (349 mg, 99%), which was used in the next step without further purification. MS (ESI): m/z = 246.2 [M+H] ⁺ .

Intermediate: 4-(5-( trifluoromethoxy ) pyridin -2- yl ) hexahydropyridine- 1- carboxylic acid tert-butyl ester in a 25 mL three-necked drying flask, the zinc powder (193 mg, 2.38 mmol) combined with 1.5 mL DMA (on molecular sieve) to give a gray suspension. Stir the mixture at room temperature while adding 7:5 of chlorotrimethylsilane (32 ul) and 1,2-dibromoethane (22 ul) at a rate to maintain the temperature below 65°C (slightly exothermic) Solution of v/v mixture in DMA (1 mL). The resulting slurry was stirred for 20 minutes. A solution of tert-butyl 4-iodohexahydropyridine-1-carboxylate (771 mg, 2.48 mmol) in 2 mL DMA was slowly added to the mixture. Then, the resulting reaction mixture was stirred at room temperature for 30 minutes. Without stirring, the reaction was allowed to stand for 15 min for decantation. In a 25 mL three-necked flask, combine 2-bromo-5-(trifluoromethoxy)pyridine (300 mg, 172 µl, 1.24 mmol) with 1.5 mL DMA to obtain a colorless solution, and add copper (I) iodide (23.6 mg, 124 µmol) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium(II) complex with dichloromethane (50.6 mg, 62 µmol). The reaction mixture was degassed with argon, freshly prepared zinc reagent solution was added, degassed again with argon, and the reaction mixture was stirred at 80°C for 6 hours. The reaction mixture was quenched with 10 mL saturated NH ₄ Cl, and extracted twice with EtOAc (40 mL each time). The organic layer was washed with brine. The organic layers were combined, dried over MgSO ₄ and concentrated in vacuo. Purification by SiO ₂ flash chromatography using 0% to 50% n-heptane/EtOAc in 35 min gave the desired product (387 mg, 90.1%) as a light yellow oil. MS (ESI): m/z = 347.1 [M+H] ⁺ .

BB133 4-((2- chloro- 4- fluorophenyl ) difluoromethyl ) hexahydropyridine hydrochloride in a 25 mL tube, place 4-((2-chloro-4-fluorophenyl)difluoromethyl Yl) hexahydropyridine-1-carboxylic acid tert-butyl ester (0.363 g, 998 µmol) was dissolved in DCM (2 mL), and 2 M HCl (4.99 mL, 9.98 mmol) in ether was added. The reaction was stirred at room temperature overnight. The solvent was removed in vacuo to obtain 296 mg (99%) of crude product as a light brown solid. It was used without further purification. MS (ESI): m/z = 264.08 [M+H] ⁺ .

Intermediate 4-((2- chloro- 4- fluorophenyl ) difluoromethyl ) hexahydropyridine- 1- carboxylic acid tert-butyl ester to 4-(2-chloro-4-fluorobenzyl) hexa A solution of tert-butyl hydropyridine-1-carboxylate (0.48 g, 1.4 mmol) in DCM (4 mL) was added DAST (7.92 g, 49.2 mmol). The reaction mixture was stirred at 45°C for ten days. The reaction mixture was poured into 15 mL H ₂ O + ice and extracted with DCM (2×20 mL). The organic layers were combined, washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 20 g, 0% to 20% EtOAc in n-heptane): 363 mg (71%), light brown oil, desired product. MS (ESI): m/z = 363.1 [M+H] ⁺ .

BB134 3- ethyl -5-( hexahydropyridin- 4 -yl ) pyridine dihydrochloride in a 25 mL tube, place 4-(5-ethylpyridin-3-yl)hexahydropyridine-1-carboxylic acid first Tributyl ester (295 mg, 1.02 mmol) was dissolved in DCM (3 mL), and 2 M HCl (3.05 mL, 6.09 mmol) in diethyl ether was added. The reaction was stirred at room temperature for 4 h. The solvent was removed in vacuo to obtain 266 mg (99%) of crude product as a yellow solid. It was used without further purification. MS (ESI): m/z = 191.1 [M+H] ⁺ .

Intermediate 4-(5 -ethylpyridin- 3 -yl ) hexahydropyridine- 1- carboxylic acid tert-butyl ester in a 25 mL three-necked dry flask, the zinc powder (234 mg, 3.58 mmol) and 1.5 mL DMA Combine (on molecular sieve) to give a gray suspension. Stir the mixture at room temperature while adding 7:5 of chlorotrimethylsilane (32 ul) and 1,2-dibromoethane (22 ul) at a rate to maintain the temperature below 65°C (slightly exothermic) Solution of v/v mixture in DMA (1 mL). The resulting slurry was stirred for 20 minutes. A solution of tert-butyl 4-iodohexahydropyridine-1-carboxylate (937 mg, 3.01 mmol) in 2 mL DMA was slowly added to the mixture. Then, the resulting reaction mixture was stirred at room temperature for 30 minutes. Without stirring, the reaction was allowed to stand for 15 min for decantation. In a 25 mL three-necked flask, combine 3-bromo-5-ethylpyridine (280 mg, 1.5 mmol) with 1.5 mL DMA to obtain a colorless solution. Add copper(I) iodide (28.7 mg, 150 µmol) and The complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (61.5 mg, 75.2 µmol). The reaction mixture was degassed with argon, freshly prepared zinc reagent solution was added, degassed with argon again, and the reaction mixture was stirred at 80°C for 2.5 hours. The reaction mixture was quenched with 10 mL of saturated aqueous NH ₄ Cl solution and extracted with EtOAc (40 mL each time). The organic layer was washed with brine. The organic layers were combined, dried over MgSO ₄ and concentrated in vacuo. Purification by SiO ₂ flash chromatography using 0% to 60% n-heptane/EtOAc within 40 min gave the desired product (299 mg, 68.4%) as a light yellow oil. MS (ESI): m/z = 291.2 [M+H] ⁺ .

BB135 5-(1,1 -difluoroethyl )-2-( hexahydropyridin- 4 -yl ) pyridine dihydrochloride in a 25 mL tube, place 4-(5-(1,1-difluoroethyl Yl)pyridin-2-yl)hexahydropyridine-1-carboxylic acid tert-butyl ester (416 mg, 1.27 mmol) was dissolved in DCM (3 mL), and 2 M HCl (3.82 mL, 7.65 mmol) in ether was added ). The reaction was stirred at room temperature for 4 h. The solvent was removed in vacuo to obtain 381 mg (99%) of crude product as a yellow solid. It was used without further purification. MS (ESI): m/z = 227.2 [M+H] ⁺ .

Intermediate: 4-(5-(1,1 -difluoroethyl ) pyridin -2- yl ) hexahydropyridine- 1- carboxylic acid tert-butyl ester in a 25 mL three-necked drying flask, the zinc powder (210 mg, 3.22 mmol) combined with 1.5 mL DMA (on a molecular sieve) to obtain a gray suspension. Stir the mixture at room temperature while adding 7:5 of chlorotrimethylsilane (32 ul) and 1,2-dibromoethane (22 ul) at a rate to maintain the temperature below 65°C (slightly exothermic) Solution of v/v mixture in DMA (1 mL). The resulting slurry was stirred for 20 minutes. A solution of tert-butyl 4-iodohexahydropyridine-1-carboxylate (841 mg, 2.7 mmol) in 2 mL of DMA was slowly added to the mixture. Then, the resulting reaction mixture was stirred at room temperature for 30 minutes. Without stirring, the reaction was allowed to stand for 15 min for decantation. In a 25 mL three-necked flask, combine 2-bromo-5-(1,1-difluoroethyl)pyridine (300 mg, 1.35 mmol) with 1.5 mL of DMA to obtain a colorless solution, and add copper (I) iodide (25.7 mg, 135 µmol) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium(II) complex with dichloromethane (55.2 mg, 67.6 µmol). The reaction mixture was degassed with argon, freshly prepared zinc reagent solution was added, degassed with argon again, and the reaction mixture was stirred at 80°C for 2.5 hours. The reaction mixture was quenched with 10 mL saturated NH ₄ Cl, and extracted twice with EtOAc (40 mL each time). The organic layer was washed with brine. The organic layers were combined, dried over MgSO ₄ and concentrated in vacuo. Purification by SiO ₂ flash chromatography using 0% to 50% n-heptane/EtOAc within 40 min gave the desired product as a yellow oil (419 mg, 85%). MS (ESI): m/z = 327.2 [M+H] ⁺ .

BB136 (4aR,8aS)-6-(4-(5-(1,1 -difluoroethyl ) pyridin -2- yl )-3 -methylhexahydropyridine- 1- carbonyl ) hexahydro -2H- pyridine And [4,3-b][1,4] oxazine -3(4H) -one title compound is similar to method A2, from BB14a and 5-(1,1-difluoroethyl)-2-(3 -Methyl-4-hexahydropyridyl)pyridine dihydrochloride. MS (ESI): m/z = 423.4 [M+H] ⁺ .

Intermediate: a) 5-(1,1 -difluoroethyl )-2-(3- methyl- 4 -hexahydropyridyl ) pyridine dihydrochloride in a 25 mL tube, place 4-(5- (1,1-difluoroethyl)pyridin-2-yl)-3-methylhexahydropyridine-1-carboxylic acid tert-butyl ester (265 mg, 778 µmol) was dissolved in DCM (3 mL), and Add 2 M HCl (3.11 mL, 6.23 mmol) in ether. The reaction was stirred at room temperature for 4 h. The solvent was removed in vacuo to obtain the crude product as a light yellow solid (242 mg, 99%). It was used without further purification. MS (ESI): m/z = 241.2 [M+H] ⁺ . b) 4-[5-(1,1 -difluoroethyl )-2- pyridyl ]-3 -methyl - hexahydropyridine- 1- carboxylic acid tert-butyl ester in a 25 mL three-necked dry flask, The zinc powder (140 mg, 2.14 mmol) was combined with 1.5 mL DMA (on the molecular sieve) to obtain a gray suspension. Stir the mixture at room temperature while adding 7:5 of chlorotrimethylsilane (32 ul) and 1,2-dibromoethane (22 ul) at a rate to maintain the temperature below 65°C (slightly exothermic) Solution of v/v mixture in DMA (1 mL). The resulting slurry was stirred for 20 minutes. A solution of tert-butyl 4-iodo-3-methylhexahydropyridine-1-carboxylate (586 mg, 1.8 mmol) in 2 mL DMA was slowly added to the mixture. Then, the resulting reaction mixture was stirred at room temperature for 30 minutes. Without stirring, the reaction was allowed to stand for 15 min for decantation. In a 25 mL three-necked flask, combine 2-bromo-5-(1,1-difluoroethyl)pyridine (200 mg, 901 µmol, CAS RN 1211521-60-6) with 1.5 mL DMA to obtain a colorless solution , Add the complex of copper(I) iodide (17.2 mg, 90.1 µmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (36.8 mg, 45 µmol). The reaction mixture was degassed with argon, freshly prepared zinc reagent solution was added, degassed with argon again, and the reaction mixture was stirred at 80°C for 3 hours. The reaction mixture was quenched with 10 mL saturated NH ₄ Cl, and extracted twice with EtOAc (40 mL each time). The organic layer was washed with brine. The organic layers were combined, dried over MgSO ₄ and concentrated in vacuo. Purification by SiO ₂ flash chromatography using n-heptane/EtOAc (0% to 50% in 35 min) gave the desired product (266 mg, 87%) as a yellow oil. MS (ESI): m/z = 341.2 [M+H] ⁺ .

BB137 1-(2,2,2- trifluoro- 1 -phenyl - ethyl ) hexahydropyrazine hydrochloride in a 25 mL tube, place 4-(2,2,2-trifluoro-1-benzene Ethyl) hexahydropyrazine-1-carboxylic acid tert-butyl ester (155 mg, 450 µmol) was dissolved in DCM (2 mL), and 2 M HCl (1.8 mL, 3.6 mmol) in ether was added. The reaction was stirred at room temperature for 4 h. The solvent was removed in vacuo to obtain 127 mg (100%) of crude product as a light brown solid. It was used without further purification. MS (ESI): m/z = 245.3 [M+H] ⁺ .

Intermediate 4-(2,2,2- trifluoro- 1 -phenyl - ethyl ) hexahydropyrazine- 1- carboxylic acid tert-butyl ester To a 100 mL dry flask with a separator and N ₂ bubbler Add tert-butyl hexahydropyrazine-1-carboxylate (1000 mg, 5.37 mmol), triethylamine (1.63 g, 2.25 mL, 16.1 mmol), 2,2,2-trifluoro-1-phenylethyl 1-one (935 mg, 754 µl, 5.37 mmol) and DCM (33 mL). 1 M titanium tetrachloride (2.68 mL, 2.68 mmol) in DCM was added via syringe. The reaction was stirred for 18 h, carefully quenched with a solution of NaCNBH ₃ (sodium cyanoborohydride (1.01 g, 16.1 mmol) in methanol (12.8 mL, 316 mmol) and stirred for 15 min. Using 5 M NaOH (0.5 mL) The reaction was basified to pH 13, extracted with DCM (2×60 mL), dried (Na ₂ SO ₄ ) and evaporated to produce a yellow oil (2 g). By flash chromatography on SiO ₂ , used in An EtOAc gradient in n-heptane (0% to 30% in 40 min) was purified to give the desired product (156 mg, 8.4%) as a light yellow oil. MS (ESI): m/z = 345.2 [ M+H] ⁺ .

BB138 1-[1-(2,4 -difluorophenyl )-2,2,2- trifluoro - ethyl ] hexahydropyrazine ; hydrochloride in a 25 mL tube, place 4-(2,2 ,2-trifluoro-1-phenylethyl)hexahydropyrazine-1-carboxylic acid tert-butyl ester (330 mg, 868 µmol) was dissolved in DCM (2 mL) and added to 2 M in ether HCl (2.6 mL, 5.1 mmol). The reaction was stirred at room temperature for 4 h. The solvent was removed in vacuo to obtain 266 mg (97%) of crude product as a brown viscous oil. It was used without further purification. MS (ESI): m/z = 282.3 [M+H] ⁺ .

Intermediate 4-[1-(2,4 -difluorophenyl )-2,2,2- trifluoro - ethyl ] hexahydropyrazine- 1- carboxylic acid tert-butyl ester To have a separator and N ₂ A 100 mL dry flask in a bubbler was charged with tert-butyl hexahydropyrazine-1-carboxylate (1000 mg, 5.37 mmol), triethylamine (1.63 g, 2.25 mL, 16.1 mmol), 1-(2,4 -Difluorophenyl)-2,2,2-trifluoroethyl-1-one (1.13 g, 5.37 mmol) and DCM (33 mL). 1 M titanium tetrachloride (2.68 mL, 2.68 mmol) in DCM was added via syringe. The reaction was stirred for 18 h, carefully quenched with a solution of NaCNBH ₃ (sodium cyanoborohydride (1.01 g, 16.1 mmol) in methanol (4.3 mL, 107 mmol) and stirred for 6 hours. Saturated NaHCO ₃ (10 mL) to basify the reaction. The obtained insoluble material was filtered off using celite, the filtrate was extracted with DCM (2×60 mL), dried (Na ₂ SO ₄ ) and evaporated to yield a yellow oil (2.1 g) Purified by SiO ₂ flash chromatography, 0% to 20% n-heptane/EtOAc in 40 min to give the desired product (340 mg, 13.3%) as a yellow oil. MS (ESI): m/ z = 381.1 [M+H] ⁺ .

BB139 2 -cyclopropyl- 4-(4- hexahydropyridyl ) pyridine dihydrochloride in a 25 mL tube, place 4-(2-cyclopropylpyridin-4-yl)hexahydropyridine-1-carboxylic acid The third butyl ester (278 mg, 919 µmol) was dissolved in DCM (2 mL), and 2 M HCl (2.76 mL, 5.52 mmol) in ether was added. The reaction was stirred at room temperature for 4 h. The solvent was removed in vacuo to obtain 250 mg (99%) of crude product as a light yellow solid. It was used without further purification. MS (ESI): m/z = 202.4 [M+H] ⁺ .

Intermediate 4-(2 -cyclopropyl- 4- pyridyl ) hexahydropyridine- 1- carboxylic acid tert-butyl ester in a 25 mL three-necked dry flask, the zinc powder (196 mg, 3 mmol) and 1.5 mL The DMA is combined (on the molecular sieve) to obtain a gray suspension. Stir the mixture at room temperature while adding 7:5 of chlorotrimethylsilane (32 ul) and 1,2-dibromoethane (22 ul) at a rate to maintain the temperature below 65°C (slightly exothermic) Solution of v/v mixture in DMA (1 mL). The resulting slurry was stirred for 20 minutes. A solution of tert-butyl 4-iodohexahydropyridine-1-carboxylate (786 mg, 2.52 mmol) in 2 mL DMA was slowly added to the mixture. Then, the resulting reaction mixture was stirred at room temperature for 30 minutes. Without stirring, the reaction was allowed to stand for 15 min for decantation. In a 25 mL three-necked flask, combine 4-bromo-2-cyclopropylpyridine (250 mg, 1.26 mmol) with 1.5 mL DMA to obtain a colorless solution, add copper(I) iodide (24 mg, 126 µmol) And [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (51.1 mg, 63.1 µmol). The reaction mixture was degassed with argon, freshly prepared zinc reagent solution was added, degassed with argon again, and the reaction mixture was stirred at 80°C for 3 hours. The reaction mixture was quenched with 10 mL of saturated aqueous NH ₄ Cl solution and extracted with EtOAc (40 mL each time). The organic layer was washed with brine. The organic layers were combined, dried over MgSO ₄ and concentrated in vacuo. Purification by SiO ₂ flash chromatography using 0% to 60% n-heptane/EtOAc in 45 min gave the desired product (278 mg, 73%) as a light yellow oil. MS (ESI): m/z = 303.2 [M+H] ⁺ .

BB140 3- methyl -5-(4- hexahydropyridyl )-2-( trifluoromethyl ) pyridine dihydrochloride in a 25 mL tube, place 4-(5-methyl-6-(trifluoro Methyl)pyridin-3-yl)hexahydropyridine-1-carboxylic acid tert-butyl ester (360 mg, 1.05 mmol) was dissolved in DCM (3 mL), and 2 M HCl (2.61 mL, 5.23 mmol). The reaction was stirred at room temperature for 4 h. The solvent was removed in vacuo to obtain 314 mg (95%) of crude product as a white solid. It was used without further purification. MS (ESI): m/z = 245.2 [M+H] ⁺ .

Intermediate 4-[5 -methyl -6-( trifluoromethyl )-3- pyridyl ] hexahydropyridine- 1- carboxylic acid tert-butyl ester in a 25 mL three-necked drying flask, the zinc powder (182 mg, 2.78 mmol) was combined with 1.5 mL DMA (on molecular sieve) to obtain a gray suspension. Stir the mixture at room temperature while adding 7:5 of chlorotrimethylsilane (32 ul) and 1,2-dibromoethane (22 ul) at a rate to maintain the temperature below 65°C (slightly exothermic) Solution of v/v mixture in DMA (1 mL). The resulting slurry was stirred for 20 minutes. A solution of tert-butyl 4-iodohexahydropyridine-1-carboxylate (726 mg, 2.33 mmol) in 2 mL of DMA was slowly added to the mixture. Then, the resulting reaction mixture was stirred at room temperature for 30 minutes. Without stirring, the reaction was allowed to stand for 15 min for decantation. In a 25 mL three-necked flask, combine 5-bromo-3-methyl-2-(trifluoromethyl)pyridine (280 mg, 1.17 mmol) with 1.5 mL of DMA to obtain a colorless solution. Add copper iodide (I ) (22.2 mg, 117 µmol) and the complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (48 mg, 58 µmol). The reaction mixture was degassed with argon, freshly prepared zinc reagent solution was added, degassed again with argon, and the reaction mixture was stirred at 70°C for 2.5 hours. The reaction mixture was quenched with 10 mL saturated NH ₄ Cl, and extracted twice with EtOAc (40 mL each time). The organic layer was washed with brine. The organic layers were combined, dried over MgSO ₄ and concentrated in vacuo. Purification by SiO ₂ flash chromatography using 0% to 50% n-heptane/EtOAc within 40 min gave the desired product (360 mg, 90%) as a white crystalline solid. MS (ESI): m/z = 345.2 [M+H] ⁺ .

BB141 4-(4 -Hexahydropyridyl )-5,6,7,8- tetrahydroquinoline dihydrochloride in a 25 mL tube, place 4-(5,6,7,8-tetrahydroquinoline -4-yl)hexahydropyridine-1-carboxylic acid tert-butyl ester (255 mg, 806 µmol) was dissolved in DCM (3 mL), and 2 M HCl (2.01 mL, 4.03 mmol) in ether was added. The reaction was stirred at room temperature for 8 h. The solvent was removed in vacuo to obtain 230 mg (99%) of crude product as a light yellow solid. It was used without further purification. MS (ESI): m/z = 217.4 [M+H] ⁺ .

Intermediate 4-(5,6,7,8 -tetrahydroquinolin- 4 -yl ) hexahydropyridine- 1- carboxylic acid tert-butyl ester in a 25 mL three-necked dry flask, the zinc powder (177 mg, 2.71 mmol) was combined with 1.5 mL DMA (on molecular sieve) to obtain a gray suspension. Stir the mixture at room temperature while adding 7:5 of chlorotrimethylsilane (32 ul) and 1,2-dibromoethane (22 ul) at a rate to maintain the temperature below 65°C (slightly exothermic) Solution of v/v mixture in DMA (1 mL). The resulting slurry was stirred for 20 minutes. A solution of tert-butyl 4-iodohexahydropyridine-1-carboxylate (734 mg, 2.36 mmol) in 2 mL DMA was slowly added to the mixture. Then, the resulting reaction mixture was stirred at room temperature for 30 minutes. Without stirring, the reaction was allowed to stand for 15 min for decantation. In a 25 mL three-necked flask, combine 4-bromo-5,6,7,8-tetrahydroquinoline (250 mg, 1.18 mmol) with 1.5 mL DMA to obtain a colorless solution, and add copper (I) iodide ( 22.4 mg, 118 µmol) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium(II) complex with dichloromethane (48 mg, 58 µmol). The reaction mixture was degassed with argon, freshly prepared zinc reagent solution was added, degassed again with argon, and the reaction mixture was stirred at 75°C for 2.5 hours. The reaction mixture was quenched with 10 mL saturated NH ₄ Cl, and extracted twice with EtOAc (40 mL each time). The organic layer was washed with brine. The organic layers were combined, dried over MgSO ₄ and concentrated in vacuo. Purification by SiO ₂ flash chromatography, using an EtOAc gradient in n-heptane (0% to 70% over 40 min), gave the desired product (255 mg, 68.4%) as a colorless viscous oil. MS (ESI): m/z = 317.3 [M+H] ⁺ .

BB142 3-[2- fluoro- 4-( trifluoromethyl ) phenyl ] azetidine trifluoroacetate to 3-(2-fluoro-4-(trifluoromethyl)phenyl)azacyclo A solution of tert-butyl butane-1-carboxylate (0.078 g, 244 µmol) in DCM (2 mL) was added TFA (94.1 µl, 1.22 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo (co-evaporated with toluene) to give the desired product (85 mg, 100%) as a colorless oil. MS (ESI): m/z = 220.1 [M+H] ⁺ .

Intermediate 3-[2- fluoro- 4-( trifluoromethyl ) phenyl ] azetidine- 1- carboxylic acid tert-butyl ester Add a photocatalyst (Ir[dF( CF3)ppy]2(dtbpy))PF6 (6.93 mg, 6.17 µmol), 1-bromo-2-fluoro-4-(trifluoromethyl)benzene (150 mg, 88.5 µl, 617 µmol), 3-bromonitrogen Heterocyclobutane-1-carboxylic acid tert-butyl ester (219 mg, 152 µl, 926 µmol), ginseng (trimethylsilyl) silane (153 mg, 617 µmol) and anhydrous sodium carbonate (131 mg, 1.23 mmol ). The vial was sealed and placed under argon, after which DME (5 mL) was added. Add NiCl ₂ glyme (1.36 mg, 6.17 µmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (1.66 mg, 6.17 µmol) to separate vials. The front catalyst vial was sealed, purged with argon, and then DME (2 mL) was added thereto. The pre-catalyst vial was sonicated for 5 min, after which 1 mL (0.5 mol% catalyst, 0.005 eq) was injected into the reaction vessel. The solution was degassed by purging with argon. The reaction was stirred and irradiated with a 420 nm lamp for 5 hours. The reaction was quenched by exposure to air and concentrated in vacuo. By flash chromatography (silica gel, 50 g, 0% to 50% EtOAc gradient in n-heptane) and second flash chromatography (silica gel, 50 g, 0% to 20% EtOAc in n-heptane) Purify the crude material. The product was obtained as a colorless liquid (197 mg, 44%). MS (ESI): m/z = 264.2 [MC ₄ H ₈ +H] ⁺ .

BB143 4-(1-(4- fluorophenyl )-1H- pyrazol- 3 -yl ) hexahydropyridine hydrochloride in a 25 mL tube, place 4-(1-(4-fluorophenyl)-1H -Pyrazol-3-yl)hexahydropyridine-1-carboxylic acid tert-butyl ester (100 mg, 290 µmol) was dissolved in DCM (3 mL) and added 2 M HCl (1.16 mL, 2.23 mmol in ether) ). The reaction was stirred at room temperature for 6 h. The solvent was removed in vacuo to obtain the crude product as a light yellow solid (81 mg, 99%). The compound was used without further purification. MS (ESI): m/z = 246.2 [M+H] ⁺ .

酸(217 mg, 1.55 mmol)及乙酸銅(II) (325 mg, 1.79 mmol)。將所得綠色溶液在室溫下攪拌60小時。將溶劑在真空中去除，用乙酸乙酯/水/飽和NaCl萃取殘餘物，經MgSO₄ 乾燥，過濾且將溶劑在真空中去除。藉由急速層析(矽膠，在40分鐘內於正庚烷中之0%至40% EtOAc梯度)純化粗製材料。獲得呈無色黏性油狀物之產物(290 mg, 70%)。MS (ESI): m/z = 290.2 [M-C₄ H₈ +H]⁺ 。 Intermediate : a) 4-(1H- pyrazol- 3 -yl ) hexahydropyridine- 1- carboxylic acid tert-butyl ester 4-acetoacetylhexahydropyridine-1-carboxylic acid tert-butyl ester (620 mg , 2.73 mmol) was combined with N,N-dimethylformamide dimethyl acetal (6.7 g, 54.6 mmol) and heated at 100°C for 15 hours. LCMS showed complete reaction. The reaction mixture was directly concentrated in vacuo, and the residue was combined with EtOH (8 mL) and hydrazine dihydrochloride (344 mg, 3.27 mmol). The mixture was stirred at reflux for 1.5 hours. LCMS again showed a complete reaction. The reaction mixture was concentrated to give the crude product as a light yellow solid (650 mg, 95%). It was used in the next step without further purification. b) 4-[1-(4- fluorophenyl ) pyrazol- 3 -yl ] hexahydropyridine- 1- carboxylic acid tert-butyl ester in a 100 mL flask purged with argon, place 4-(1H- Pyrazol-3-yl)hexahydropyridine-1-carboxylic acid tert-butyl ester (300 mg, 1.19 mmol) was suspended in DMF (8 mL), and pyridine (386 µl, 4.77 mmol), (4-fluorobenzene base)

Acid (217 mg, 1.55 mmol) and copper(II) acetate (325 mg, 1.79 mmol). The resulting green solution was stirred at room temperature for 60 hours. The solvent was removed in vacuo, ethyl acetate / water / saturated NaCl residue was extracted, dried over MgSO _4, filtered and the solvent removed in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 40% EtOAc gradient in n-heptane over 40 minutes). The product was obtained as a colorless viscous oil (290 mg, 70%). MS (ESI): m/z = 290.2 [MC ₄ H ₈ +H] ⁺ .

BB144 4-(4 -Hexahydropyridyl )-3-( trifluoromethyl ) pyrazine hydrochloride in a 25 mL tube, place 4-(3-(trifluoromethyl)pyrazine-4-yl) The third butyl hexahydropyridine-1-carboxylate (180 mg, 543 µmol) was dissolved in DCM (1 mL), and 2 M HCl (2.72 mL, 5.43 mmol) in ether was added. The reaction was stirred at room temperature for 6 h. The solvent was removed in vacuo to obtain 145 mg (100%) of crude product as a yellow solid. It was used without further purification. MS (ESI): m/z = 232.2 [M+H] ⁺ .

Intermediate 4-(3-( trifluoromethyl ) pyridazin- 4 -yl ) hexahydropyridine- 1- carboxylic acid tert-butyl ester (1-(third butoxycarbonyl)hexahydropyridine-4- Base) potassium trifluoroborate (649 mg, 2.23 mmol), silver nitrate (68.8 mg, 405 µmol) and potassium persulfate (2.74 g, 10.1 mmol) were added to a reaction tube equipped with a stir bar. Add 1,2-dichloroethane (2 mL), water (2 mL), 3-(trifluoromethyl)pyrazine (300 mg, 2.03 mmol) and TFA (462 mg, 312 µl, 4.05 mmol) successively. And seal the tube. The reaction was vigorously stirred at room temperature for 24 h. The reaction mixture was then poured into a 1/1 v/v mixture of 20 mL saturated aqueous NaHCO ₃ solution and 5% NaS ₂ O ₃ aqueous solution, and the resulting solution was extracted three times with DCM. The combined organic layers were dried (MgSO4) and evaporated to obtain the crude product. Purification by SiO ₂ flash chromatography, 0% to 80% n-heptane/EtOAc in 35 min, gave the desired product as a yellow viscous oil (180 mg, 80% pure, 21.5%). Regioisomers were confirmed by NMR. MS (ESI): m/z = 332.2 [M+H] ⁺ .

BB145 (4aR,8aS)-6-(3-(4 -hydroxyphenyl ) azetidine- 1- carbonyl ) hexahydro -2H- pyrido [4,3-b][1,4] oxazine -3(4H) -one This compound is obtained from 3-(4-hydroxyphenyl)azetidine 4-toluenesulfonate similar to method A4. Light brown solid. MS (ESI): m/z = 332.2 [M+H] ⁺ .

Intermediate a) 3-(4 -Hydroxyphenyl ) azetidine 4 -toluenesulfonate, 3-(4-(third butoxy)phenyl)azetidine-1-carboxylic acid A mixture of tributyl ester (70 mg, 229 µmol) and 4-toluenesulfonic acid hydrate (52.3 mg, 275 µmol) in EtOAc (1 mL) was stirred at reflux for 30 min. The mixture was evaporated to provide the desired product, which was used in the next step without further purification. b) 3-(4-( T-butoxy ) phenyl ) azetidine- 1- carboxylic acid tert-butyl ester This compound is similar to Method A7, from 1-bromo-4-(tert-butyl Oxygen)benzene (CAS RN 60876-70-2) was obtained to provide the desired compound as a colorless solid. MS (ESI): m/z = 250.2 [MC ₄ H ₈ +H] ⁺ .

BB146 3-(3,4 -dimethylphenyl ) azetidine 4 -toluenesulfonate This compound is similar to BB28, from 3-(3,4-dimethylphenyl)azetidine The third butyl alkane-1-carboxylate is obtained as the desired compound as a colorless solid. MS (ESI): m/z = 162.1 [M+H] ⁺ .

酸以產生呈無色油狀物之期望化合物來獲得。MS (ESI): m/z = 206.1 [M-C₄ H₈ +H]⁺ 。 Intermediate 3-(3,4 -Dimethylphenyl ) azetidine- 1- carboxylic acid tert-butyl ester This compound is similar to BB35 intermediate, from (3,4-dimethylphenyl)

The acid is obtained as the desired compound as a colorless oil. MS (ESI): m/z = 206.1 [MC ₄ H ₈ +H] ⁺ .

BB147 3-(4- third butoxyphenyl ) azetidine 4 -toluenesulfonate similar to BB28, from 3-(4- third butoxyphenyl) azetidine-1 -Tert-butyl formate (BB145, intermediate b) at room temperature to obtain the compound as a colorless solid. MS (ESI): m/z = 206.2 [M+H] ⁺ .

BB148 5- chloro- 1-(4- hexahydropyridyl ) indoline This compound is similar to BB26, intermediate a, from 4-(5-chloroindolin-1-yl) hexahydropyridine-1- The third butyl formate is obtained as a gray solid to provide the desired compound. MS (ESI): m/z = 237.1 [M+H] ⁺ .

Intermediate 4-(5 -chloroindolin- 1 -yl ) hexahydropyridine- 1- carboxylic acid tert-butyl ester at 25 °C to 1-Boc-4-hexahydropyridone (972.84 mg, 4.88 mmol, CAS RN 79099-07-3) in MeOH (13 mL) was added AcOH (605.43 mg, 9.76 mmol), 5-chloroindoline (500.0 mg, 3.25 mmol, CAS RN 25658-80-4) and NaBH ₃ (CN) (613.63 mg, 9.76 mmol), and the reaction mixture was stirred for 2 h. The reaction was poured into saturated aqueous NH ₄ Cl (20 mL) and extracted three times with EtOAc (20 mL each time). The combined organic layers were washed three times with water (20 mL each time) and brine (20 mL), dried over Na ₂ SO ₄ and concentrated in vacuo to provide the product as a white solid (1 g, 118.3%). MS (ESI): m/z = 337.1 [M+H] ⁺ . The crude product was used directly in the next step without further purification.

BB149 4- chloro -2-( hexahydropyridin- 4 -yl ) isoindoline hydrochloride This compound is similar to BB52, from 4-(4-chloroisoindolin-2-yl)hexahydropyridine- The third butyl 1-formate is obtained to produce the desired compound. MS (ESI): m/z = 237.2 [M+H] ⁺ . It was used in the next step without further purification.

Intermediate 4-(4 -chloroisoindolin- 2- yl ) hexahydropyridine- 1- carboxylic acid tert-butyl ester This compound is similar to the BB148 intermediate, from 4-chloroisoindoline (CAS RN 123594 -04-7) to obtain the desired compound as a gray oil. MS (ESI): m/z = 337.3 [M+H] ⁺ .

BB150 5'- chloro- 1'-(4- hexahydropyridyl ) spiro [ cyclopropane -1,3' -indoline ] This compound is similar to BB26, intermediate a, from 4-(5'-chloro Spiro[cyclopropane-1,3'-indoline]-1'-yl)hexahydropyridine-1-carboxylic acid tert-butyl ester was obtained to provide the desired compound as a yellow solid. MS (ESI): m/z = 263.1 [M+H] ⁺ .

Intermediate 4-(5' -chlorospiro [ cyclopropane -1,3' -indoline ]-1' -yl ) hexahydropyridine- 1- carboxylic acid tert-butyl ester This compound is similar to the BB148 intermediate, Obtained from 5'-chlorospiro[cyclopropane-1,3'-indoline] (CAS RN 1538359-43-1) to produce the desired compound as a pink solid. MS (ESI): m/z = 307.1 [MC ₄ H ₈ +H] ⁺ .

BB151 2-( azetidin- 3 -yl )-4 -chloroisoindoline hydrochloride This compound is similar to BB52, from 3-(4-chloroisoindolin-2-yl) nitrogen heterocycle The third butyl butane-1-carboxylate was obtained as the desired compound as a light green solid. MS (ESI): m/z = 209.2 [M+H] ⁺ .

Intermediate 3-(4 -chloroisoindolin- 2- yl ) azetidine- 1- carboxylic acid tert-butyl ester This compound is similar to BB148 intermediate, from 4-chloroisoindolin hydrochloride The salt (CAS RN 924304-73-4) was obtained as the desired compound as a colorless amorphous solid. MS (ESI): m/z = 309.2 [M+H] ⁺ .

BB152 3-[2 -methoxy- 4-(2,2,2- trifluoroethyl ) phenyl ] azetidine 2,2,2- trifluoroacetate This compound is similar to BB26, in the middle Body a, from 3-[2-methoxy-4-(2,2,2-trifluoroethyl)phenyl]azetidine-1-carboxylic acid tert-butyl ester to provide a yellow oil The desired compound is obtained. MS (ESI): m/z = 246.1 [M+H] ⁺ .

Intermediate a) 3-[2 -methoxy- 4-(2,2,2- trifluoroethyl ) phenyl ] azetidine- 1- carboxylic acid tert-butyl ester 3-[2- Methoxy-4-[2,2,2-trifluoro-1-(p-tolylsulfonyloxy)ethyl]phenyl]azetidine-1-carboxylic acid tert-butyl ester (480.0 mg, 0.930 mmol) in EtOH (24 mL) was added Pd/C (120.0 mg, 0.930 mmol), and the mixture was stirred under H ₂ atmosphere (balloon) at 20° C. for 24 h. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in EtOAc (30 mL) and washed with aqueous Na ₂ CO ₃ (20 mL), then brine, dried over Na ₂ SO ₄ and concentrated to give the desired product as a light yellow foam. (300 mg, 93.3%). MS (ESI): m/z = 290.1 [MC ₄ H ₈ +H] ⁺ . b) 3- [2- methoxy-4- [2,2,2-trifluoro-1- (p-toluene sulfonic acyl group yloxy) ethyl] phenyl] azetidine-1-carboxylic acid the third compound is butyl method similar A7, from 4-toluenesulfonic acid [1- (4-bromo-3-methoxy - phenyl) -2,2,2-trifluoro - ethyl] ester To obtain the desired compound as a light yellow oil. MS (ESI): m/z = 460.1 [MC ₄ H ₈ +H] ⁺ . c) 4- toluenesulfonic acid [1- (4-bromo-3-methoxy - phenyl) -2,2,2-trifluoro - ethyl] ester at 0 ℃ solution of 1- (4-bromo - 3-methoxy-phenyl)-2,2,2-trifluoro-ethanol (1000.0 mg, 3.51 mmol), p-toluenesulfonyl chloride (668.81 mg, 3.51 mmol) and DMAP (20.0 mg, 0.180 mmol) at TEA (708.62 mg, 7.02 mmol) was added to the solution in DCM (20 mL). The mixture was stirred at 20°C for 12 h. The mixture was washed with water and brine, dried over Na ₂ SO ₄ and concentrated to give the desired product (1.5 g, 97.4%) as a pale yellow oil. This compound was used in the next step without further purification. d) 1- (4- bromo-3-methoxy - phenyl) -2,2,2-trifluoro - ethanol at 0 ℃ of 4-bromo-3-methoxy - benzaldehyde (2.0 g, 9.3 mmol, CAS RN 43192-34-3) and trifluoromethyltrimethylsilane (1586.94 mg, 11.16 mmol) in THF (30 mL) were added TBAF/THF (0.09 mL, 0.090 mmol), the mixture Stir at 20°C for 12 h, then slowly add 1 M aqueous HCl (18.6 mL, 18.6 mmol). The mixture was stirred at 20 °C for another 2 h. The mixture was poured into water (50 mL) and extracted three times with EtOAc (30 mL each time). The combined organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated to give the desired product (2.5 g, 94.3%) as a pale yellow oil. 1H NMR (400 MHz, chloroform-d) δ = 7.57 (d, J = 8.1 Hz, 1H), 7.05 (s, 1H), 6.94 (d, J = 8.1 Hz, 1H), 5.01 (q, J = 6.5 Hz, 1H), 3.93 (s, 3H).

BB153 3-[4-(2,2 -Dimethylpropoxy ) phenyl ] azetidine 4 -toluenesulfonate This compound is similar to BB28, from 3-[4 at room temperature for 5 hours -(2,2-dimethylpropoxy)phenyl]azetidine-1-carboxylic acid tert-butyl ester to obtain the desired compound as a white solid. It is used as is in the next step.

Intermediate 3-[4-(2,2 -Dimethylpropoxy ) phenyl ] azetidine- 1- carboxylic acid tert-butyl ester This compound is similar to method A7 a, from 1-bromo- 4-(Neopentyloxy)benzene (CAS RN 528528-58-7) was obtained as the desired compound as a colorless solid. MS (ESI): m/z = 264.2 [MC ₄ H ₈ +H] ⁺ .

BB154 rac - (4aS, 8aS) - hexahydro--2H- pyrido [4,3-b] [1,4] oxazin -3 (4H) - one A mixture of rac - (4aS, 8aS) - 3-Pentoxyhexahydro-2H-pyrido[4,3-b][1,4]oxazine-6(5H)-carboxylic acid benzyl ester (125 mg, 431 µmol) was dissolved in MeOH (5 mL) in. The reaction solution was degassed in vacuum and backfilled with argon. Add Pd-C (20 mg, 188 µmol) under an argon atmosphere. Argon was evacuated from the reaction mixture, and the reaction flask was backfilled with hydrogen. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 15 h. The reaction mixture was filtered through a syringe filter and concentrated in vacuo to give the desired product (62 mg, 92.2%) as a white solid. MS (ESI): m/z = 157.098 [M+H] ⁺ .

Intermediates a) rac - (4aS, 8aS) -3- oxo-hexahydro -2H- pyrido [4,3-b] [1,4] oxazine -6 (5H) - carboxylic acid benzyl ester Racemic-(3S,4S)-3-(2-chloroacetamido)-4-hydroxyhexahydropyridine-1-carboxylic acid benzyl ester (385 mg, 1.18 mmol) in anhydrous THF at 0°C To the stirred solution in (4 mL) was added NaH (67.9 mg, 1.7 mmol). The mixture was brought to room temperature, and then stirred under an argon atmosphere for 90 min. H ₂ O (5 mL) was added, and stirring was continued at room temperature for 10 min. THF was removed from the reaction mixture in vacuo. The residue was treated with DCM, and the organic phase was washed with H ₂ O and brine, dried over Na ₂ SO ₄ , filtered and then concentrated in vacuo. The residue was purified by flash chromatography (12 g reverse phase column, 0%-100% ACN (0.1% FA) gradient in water (0.1% FA)) to give the desired product (133 mg, 38.9%). MS (ESI): m/z = 291.3 [M+H] ⁺ . b) rac - (3S, 4S) -3- ( 2- chloro-acetylglucosamine) -4-hydroxy-piperidine-1-carboxylic acid benzyl ester between at between 0 and 5 ℃ outwardly extinction Cyclo-(3S,4S)-3-amino-4-hydroxyhexahydropyridine-1-carboxylic acid benzyl ester (317 mg, 1.27 mmol, synthesized according to patent US 2011/59118 A1) and sodium acetate (208 mg, 2.53 mmol, CAS RN 127-09-3) A stirred suspension in acetone (4 mL)/H ₂ O mixture (0.5 mL) was added dropwise chloroacetamide (150 mg, 107 µL, 1.33 mmol, CAS RN 79-04-9) in acetone (3 mL). After the addition, the reaction mixture was stirred at room temperature for 1 h and then evaporated to dryness to give a yellow gum. The crude product was purified by silica gel chromatography to obtain the desired product (385 mg, 93%) as a yellow solid. MS (ESI): m /z = 325.2 [MH] ^- . Table 3

Example A The compound of formula (I) can be used as an active ingredient to produce lozenges of the following composition in a manner known per se:Per lozenge Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose20 mg 425 mg

Example B The compound of formula (I) can be used as an active ingredient to produce capsules of the following composition in a manner known per se: per capsule active ingredient 100.0 mg corn starch 20.0 mg lactose 95.0 mg talc 4.5 mg magnesium stearate 0.5 mg 220.0 mg

Claims (59)

A compound of formula (Ic),

Or a pharmaceutically acceptable salt thereof, wherein: L is selected from -CR ¹ R ² -(CH ₂ ) _p -, -(CH ₂ ) _p -CR ¹ R ² -, -OCR ³ R ⁴ -, -CR ³ R ⁴ O- and covalent bond; m is 0, n is 0 or 1 and X is CR ²⁴ ; or m is 1, n is 1 or 2 and X is CR ²⁴ or N; p is 0, 1 or 2 ; R ¹ is selected from halogen, C _1-6 -alkoxy, C _1-6 -alkyl, halo-C _1-6 -alkyl, hydroxy-C _1-6 -alkyl, C _1-6 -Alkoxy-C _1-6 -alkyl-, halo-C _1-6 -alkoxy, halo-C _1-6 -alkoxy-C _1-6 -alkyl-, cyano and Group

; And R ² is selected from hydrogen, halogen, and hydroxyl; or R ¹ and R ² together with the carbon atom to which they are attached form C _3-12 -cycloalkyl or C _{2-9 -heterocyclic} ; R ³ is selected from C _1-6 -alkyl, halo-C _1-6 -alkyl, C _3-12 -cycloalkyl and C _6-14 -aryl; and R ⁴ is hydrogen; or R ³ and R ⁴ The connected carbon atoms together form C _3-12 -cycloalkyl or C _{2-9 -heterocyclic} ; R ²⁰ is hydrogen or C _1-6 -alkyl; R ²¹ , R ²² and R ^{23 are} independently selected from hydrogen , Halogen, cyano, hydroxy, C _1-6 -alkoxy, halo-C _1-6 -alkoxy, amine-C _1-6 -alkoxy, C _1-6 -alkyl, halogen -C _1-6 -alkyl, hydroxy-C _1-6 -alkyl, (halo-C _1-6 -alkyl)-hydroxy-C _1-6 -alkyl, C _1-6 -alkoxy Carbonyl-C _1-6 -alkyl-, C _1-6 -alkoxycarbonyl-NH-C _{1-6 -alkoxy-} , C _1-6 -alkoxycarbonyl-NH-(C _{1- 6} -alkoxy) ₂ -C _1-6 -alkyl-C(O)-NH-C _{1-6 -alkoxy-} , C _1-6 -alkoxycarbonyl-NH-C _1-6- alkoxy -C _1-6 - alkyl _{-C (O) -NH-C 1-6} - alkoxy _{-, SF 5, (C 1-6} - alkyl) ₃ Si-OC _1-6 - alkoxy Radical, radical

And groups

; R ²⁴ is selected from hydrogen, halogen, hydroxy, halo-C _1-6 -alkyl and C _1-6 -alkyl; R ²⁵ and R ^{26 are} independently selected from hydrogen, halogen, C _1-6 -alkyl Group, C _1-6 -alkoxy, halo-C _1-6 -alkyl, halo-C _1-6 -alkoxy, C _1-6 -alkyl-SO ₂ -and C _3-12 -Cycloalkyl; R ²⁷ and R ^{28 are} independently selected from hydrogen, halogen, C _1-6 -alkoxy, halo-C _1-6 -alkoxy, C _1-6 -alkyl, halo- C _1-6 -alkyl, hydroxy-C _1-6 -alkyl, halogen, hydroxy, C _1-6 -alkylsulfonyl, amine, cyano, cycloalkyl-C _1-6- Alkoxy-, C _1-6 -alkyl-NH-C(O)- and cycloalkyl; A and B are independently selected from C _6-14 -aryl, C _1-13 -heteroaryl, C _3-12-- cycloalkyl, and C _2-9 - heterocyclyl group; C ^1-based C _{3- 12} - cycloalkyl or C _2-9 - heterocyclyl; C ² based C _{6- 14} - aryl group; L ² is selected from covalent bonds, -O-, -CH ₂ O-, -CH ₂ OCH ₂ -and -CH ₂ -; L ³ is selected from covalent bonds, -O-, -CH ₂ O-,- OCH ₂ -, -CH ₂ OCH ₂ -and -CH ₂ -; and L ^3a is selected from covalent bonds, -CH ₂ O-, -OCH ₂ -, -CH ₂ OCH ₂ -and -CH ₂ -. A compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (Ic) is a compound of formula (Id):

Where A, L, X, m, n and R ²⁰ to R ²³ are as defined in claim 1. A compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (Ic) is a compound of formula (Ie):

Where A, L, X, m, n and R ²⁰ to R ²³ are as defined in claim 1. A compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein: m is 0, n is 0 or 1 and X is CR ²⁴ ; or m is 1, n is 1 And X is CR ²⁴ or N. A compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein p is 0 or 1. The compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein p is 0. A compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein: R ¹ is selected from halogen, C _1-6 -alkoxy, C _1-6 -alkyl , Halo-C _1-6 -alkyl, hydroxy-C _1-6 -alkyl, C _1-6 -alkoxy-C _1-6 -alkyl-, halo-C _1-6 -alkoxy Group, halo-C _1-6 -alkoxy-C _1-6 -alkyl-, cyano and group

; And R ² is selected from hydrogen, halogen, and hydroxyl; or R ¹ and R ² together with the carbon atom to which they are attached form C _3-12 -cycloalkyl. A compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R ¹ is selected from halogen, C _1-6 -alkyl, hydroxy-C _1-6 -alkyl , C _1-6 -alkoxy-C _1-6 -alkyl-, halo-C _1-6 -alkoxy and groups

; And R ² is hydrogen or halogen. A compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R ¹ is selected from 2-methoxyethyl, methyl, 2,2,2-trifluoro Ethoxy, fluorine, 2-hydroxyethyl and groups

; And R ² is hydrogen or fluorine. A compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R ³ is C _1-6 -alkyl or halo-C _1-6 -alkyl; and R ⁴ series hydrogen. The compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R ³ is C _1-6 -alkyl; and R ⁴ is hydrogen. The compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R ³ is methyl; and R ⁴ is hydrogen. The compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R ²⁰ is hydrogen. A compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R ²¹ is selected from hydrogen, halogen, hydroxy, C _1-6 -alkoxy, halo-C _1-6 -alkoxy, C _1-6 -alkyl, halo-C _1-6 -alkyl, hydroxy-C _1-6 -alkyl, (halo-C _1-6 -alkyl)- Hydroxy-C _1-6 -alkyl, C _1-6 -alkoxycarbonyl-C _1-6 -alkyl-, C _1-6 -alkoxycarbonyl-NH-C _{1-6 -alkoxy-} , SF ₅ , (C _1-6 -alkyl) ₃ Si-OC _1-6 -alkyl-, group

And groups

, Where R ²⁷ , R ²⁸ , C ¹ , C ² , L ³ and L ^3a are as defined herein. A compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R ²¹ is selected from halogen, C _1-6 -alkoxy, halo-C _1-6- Alkoxy, C _1-6 -alkyl, halo-C _1-6 -alkyl, SF ₅ , C _6-14 -aryl and groups

, Where R ²⁷ , R ²⁸ , C ¹ and L ³ are as defined herein. A compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R ²¹ is selected from fluorine, chlorine, bromine, methyl, methoxy, third butyl, propylene Group, trifluoromethoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl Group, SF ₅ , phenyl group and group

, Where R ²⁷ , R ²⁸ , C ¹ and L ³ are as defined herein. The compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R ²² is selected from hydrogen, halogen, C _1-6 -alkoxy, halo-C _{1- 6} -alkoxy, C _1-6 -alkyl and cyano. The compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R ²² is selected from hydrogen, halogen, C _1-6 -alkoxy and halo-C _{1- 6} -alkoxy. The compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R ²² is selected from hydrogen, fluorine, chlorine, methoxy, methyl and trifluoromethyl. The compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R ²³ is hydrogen or halogen. A compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R ²³ is hydrogen or fluorine. The compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R ²⁴ is hydrogen. A compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R ²⁵ is selected from hydrogen, halogen, C _1-6 -alkyl, C _1-6 -alkoxy Group, halo-C _1-6 -alkyl, halo-C _1-6 -alkoxy, C _1-6 -alkyl-SO ₂ -and C _3-12 -cycloalkyl. A compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R ²⁵ is selected from hydrogen, halogen, C _1-6 -alkoxy and C _{3-12 -ring} alkyl. The compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R ²⁵ is selected from hydrogen, methoxy, fluorine and cyclopropyl. The compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R ²⁶ is selected from hydrogen, C _1-6 -alkyl and C _1-6 -alkoxy. The compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R ²⁶ is hydrogen or C _1-6 -alkoxy. A compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R ²⁶ is hydrogen or methoxy. A compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R ²⁷ is selected from hydrogen, halo-C _1-6 -alkoxy, C _1-6- Alkyl, halo-C _1-6 -alkyl, C _1-6 -alkyl-NH-C(O)- and halogen. A compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R ²⁷ is selected from methyl, trifluoromethoxy, trifluoromethyl, 2,2,2 -Trifluoro-1-methyl-ethoxy, 2,2,2-trifluoro-1,1-dimethyl-ethoxy, 2,2,2-trifluoroethoxy, fluorine and chlorine. The compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R ²⁸ is selected from hydrogen, C _1-6 -alkyl and halogen. A compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R ²⁸ is selected from hydrogen, methyl, fluorine and chlorine. The compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein A is C _6-14 -aryl or C _1-13 -heteroaryl. The compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein A is selected from phenyl, indol-3-yl, 2-pyridyl and 3-pyridyl. The compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein B is C _6-14 -aryl or C _1-13 -heteroaryl. The compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein B is phenyl or 1,2,4-oxadiazol-5-yl. A compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein C ¹ is selected from azetidine-1-yl, pyrrolidin-1-yl, cyclopropyl And oxetan-3-yl. The compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein C ² is phenyl. A compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein L is selected from -CR ¹ R ² -(CH ₂ ) _p -, -OCR ³ R ⁴ -, -CR ³ R ⁴ O- and covalent bonds; wherein R ¹ to R ⁴ and p are as defined herein. A compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein L ² is selected from covalent bonds, -O- and -CH ₂ -. The compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein L ² is a covalent bond. The compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein L ³ is selected from a covalent bond, -CH ₂ O- and -CH ₂ -. The compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein L ³ is a covalent bond or -CH ₂ -. The compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein L ^3a is a covalent bond or -CH ₂ -. The compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein L ^3a is a covalent bond. A compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein: m is 0, n is 0 or 1 and X is CR ²⁴ ; or m is 1, n is 1 And X is CR ²⁴ or N; L is selected from -CR ¹ R ² -(CH ₂ ) _p -, -OCHR ³ -, -CHR ³ O- and covalent bonds; p is 0 or 1; R ¹ is selected From halogen, C _1-6 -alkoxy, C _1-6 -alkyl, halo-C _1-6 -alkyl, hydroxy-C _1-6 -alkyl, C _{1-6 -alkoxy-} C _1-6 -alkyl-, halo-C _1-6 -alkoxy, halo-C _1-6 -alkoxy-C _1-6 -alkyl-, cyano and groups

; And R ² is selected from hydrogen, halogen, and hydroxyl; or R ¹ and R ² together with the carbon atom to which they are attached form C _3-12 -cycloalkyl; R ³ is C _1-6 -alkyl or halo- C _1-6 -alkyl; R ²⁰ is hydrogen or C _1-6 -alkyl; R ²¹ is selected from hydrogen, halogen, hydroxy, C _1-6 -alkoxy, halo-C _1-6 -alkyl Oxygen, C _1-6 -alkyl, halo-C _1-6 -alkyl, hydroxy-C _1-6 -alkyl, (halo-C _1-6 -alkyl)-hydroxy-C _{1- 6} -alkyl, C _1-6 -alkoxycarbonyl-C _1-6 -alkyl-, C _1-6 -alkoxycarbonyl-NH-C _{1-6 -alkoxy-} , SF ₅ , ( C _1-6 -alkyl) ₃ Si-OC _1-6 -alkyl-, group

And groups

; R ²² is selected from hydrogen, halogen, C _1-6 -alkoxy, halo-C _1-6 -alkoxy, C _1-6 -alkyl and cyano; R ²³ is hydrogen or halogen; R ²⁴ is selected from hydrogen, halogen, hydroxy and C _1-6 -alkyl; R ²⁵ is selected from hydrogen, halogen, C _1-6 -alkyl, C _1-6 -alkoxy, halo-C _{1- 6} -alkyl, halo-C _1-6 -alkoxy, C _1-6 -alkyl-SO ₂ -and C _3-12 -cycloalkyl; R ²⁶ is selected from hydrogen, C _1-6- Alkyl and C _1-6 -alkoxy; R ²⁷ is selected from hydrogen, halogen, C _1-6 -alkoxy, halo-C _1-6 -alkoxy, C _1-6 -alkyl, halo -C _1-6 - alkyl, hydroxy -C _1-6 - alkyl, halogen, hydroxy, C _1-6 - alkyl sulfonic acyl, acyl carbamoyl, cyano, cycloalkyl -C _{1 -6 -alkoxy-} and cycloalkyl; R ²⁸ is selected from hydrogen, C _1-6 -alkyl and halogen; A is C _6-14 -aryl or C _1-13 -heteroaryl; B is C _6-14 -aryl or C _1-13 -heteroaryl; C ¹ is C _3-12 -cycloalkyl or C _{2-9 -heterocyclic} ; C ² is C _6-14 -aryl; L ² is selected from covalent bonds, -O- and -CH ₂ -; L ³ is selected from covalent bonds, -CH ₂ O- and -CH ₂ -; and L ^3a is a covalent bond or -CH ₂ -. A compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein: m is 0, n is 0 or 1 and X is CH; or m is 1, n is 1 and X is CH or N; L is selected from -CR ¹ R ² -, -OCHR ³ -, -CHR ³ O- and covalent bonds; R ¹ is selected from halogen, C _1-6 -alkyl, hydroxy-C _1-6 -alkyl, C _1-6 -alkoxy-C _1-6 -alkyl-, halo-C _1-6 -alkoxy and groups

; R ² is hydrogen or halogen; R ³ is C _1-6 -alkyl; R ²⁰ is hydrogen; R ²¹ is selected from halogen, C _1-6 -alkoxy, halo-C _1-6 -alkoxy Group, C _1-6 -alkyl, halo-C _1-6 -alkyl, SF ₅ , C _6-14 -aryl and group

; R ²² is selected from hydrogen, halogen, C _1-6 -alkoxy and halo-C _1-6 -alkoxy; R ²³ is hydrogen or halogen; R ²⁵ is selected from hydrogen, halogen, C _{1- 6} -alkoxy and C _3-12 -cycloalkyl; R ²⁶ is hydrogen or C _1-6 -alkoxy; R ²⁷ is selected from hydrogen, halo-C _1-6 -alkoxy, C _{1 -6} -alkyl, halo-C _1-6 -alkyl and halogen; R ²⁸ is selected from hydrogen, C _1-6 -alkyl and halogen; A is C _6-14 -aryl or C _1-13 -Heteroaryl; B is C _6-14 -aryl or C _1-13 -heteroaryl; C ¹ is C _3-12 -cycloalkyl or C _{2-9 -heterocyclyl} ; and L ³ is common Valence bond or -CH ₂ -. A compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein: m is 0, n is 0 or 1 and X is CH; or m is 1, n is 1 and X is CH or N; L is selected from -CR ¹ R ² -, -OCHR ³ -, -CHR ³ O- and covalent bonds; R ¹ is selected from 2-methoxyethyl, methyl, 2, 2,2-trifluoroethoxy, fluorine, 2-hydroxyethyl and groups

; R ² is hydrogen or fluorine; R ³ is methyl; R ²⁰ is hydrogen; R ²¹ is selected from fluorine, chlorine, bromine, methyl, methoxy, third butyl, propyl, trifluoromethoxy , 2-fluoroethoxy, 2,2,2-trifluoroethoxy, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, SF ₅ , phenyl And groups

; R ²² is selected from hydrogen, fluorine, chlorine, methoxy, methyl and trifluoromethyl; R ²³ is hydrogen or fluorine; R ²⁵ is selected from hydrogen, methoxy, fluorine and cyclopropyl; R ²⁶ Is hydrogen or methoxy; R ²⁷ is selected from methyl, trifluoromethoxy, trifluoromethyl, 2,2,2-trifluoro-1-methyl-ethoxy, 2,2,2- Trifluoro-1,1-dimethyl-ethoxy, 2,2,2-trifluoroethoxy, fluorine and chlorine; R ²⁸ is selected from hydrogen, methyl, fluorine and chlorine; A is selected from benzene Group, indol-3-yl, 2-pyridyl and 3-pyridyl; B is phenyl or 1,2,4-oxadiazol-5-yl; C ¹ is selected from azetidine-1- Group, pyrrolidin-1-yl, cyclopropyl and oxetan-3-yl; and L ³ is a covalent bond or -CH ₂ -. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 is selected from the compounds disclosed in Table 1 and Table 3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, which is selected from: Racemic-cis-6-(4-(5-chloro-1-(cyclopropylmethyl)-1H-indol-3-yl)hexahydropyridine-1-carbonyl)hexahydro-2H-pyridine And [4,3-b][1,4]oxazin-3(4H)-one; Racemic-cis-6-(4-(5-chloro-1-methyl-1H-indol-3-yl)hexahydropyridine-1-carbonyl)hexahydro-2H-pyrido[4,3 -b][1,4]oxazin-3(4H)-one; Racemic-cis-6-(4-(1-(4-fluorophenyl)-3-methoxypropyl)hexahydropyridine-1-carbonyl)hexahydro-2H-pyrido[4,3 -b][1,4]oxazin-3(4H)-one; Racemic-cis-6-(4-((4-chlorophenyl)(phenyl)methyl)hexahydropyrazine-1-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4]oxazine-3(4H)-one; (+)-cis-6-(4-(bis(4-fluorophenyl)methyl)hexahydropyrazine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1, 4] Oxazine-3(4H)-one; (+)- or (-)-cis-6-(4-(5-chloro-1-cyclopropyl-1H-indol-3-yl)hexahydropyridine-1-carbonyl)hexahydro-2H- Pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (-)-cis-6-(4-(5-chloro-1-(oxetan-3-yl)-1H-indol-3-yl)hexahydropyridine-1- Carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; Racemic-cis-6-(4-(1-(4-fluorophenyl)-3-hydroxypropyl)hexahydropyridine-1-carbonyl)hexahydro-2H-pyrido[4,3-b ][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-(difluoro(4-(trifluoromethyl)phenyl)methyl)hexahydropyridine-1-carbonyl)hexahydro-2H-pyrido(4,3-b ][1,4]oxazin-3(4H)-one; (+) or (-)-cis-6-(4-((R or S)-1-(2-chloro-4-fluorophenoxy)ethyl)hexahydropyridine-1-carbonyl)hexahydro -2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+) or (-)-cis-6-(4-((4-chlorophenyl)difluoromethyl)hexahydropyridine-1-carbonyl)hexahydro-2H-pyrido[4,3-b ][1,4]oxazin-3(4H)-one; (+) or (-)-cis-6-(4-((2-chloro-4-fluorophenyl)difluoromethyl)hexahydropyridine-1-carbonyl)hexahydro-2H-pyrido[4 ,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((R or S)-1-(4-(trifluoromethyl)phenyl)ethyl)hexahydropyridine-1-carbonyl)hexahydro-2H-pyrido [4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((S or R)-(4-fluorophenyl)(2,2,2-trifluoroethoxy)methyl)hexahydropyridine-1-carbonyl)hexa Hydrogen-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-[4-[(S or R)-(4-fluorophenyl)-(3-methoxyphenyl)methyl]hexahydropyridine-1-carbonyl]-4,4a ,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-(4-((R or S)-(4-fluorophenyl)(3-methoxyphenyl)methyl)hexahydropyridine-1-carbonyl)hexahydro-2H- Pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((S or R)-(3-(2-fluoroethoxy)phenyl)(phenyl)methyl)hexahydropyridine-1-carbonyl)hexahydro- 2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((3-cyclopropyl-1,2,4-oxadiazol-5-yl)(4-fluorophenyl)methyl)hexahydropyridine-1-carbonyl ) Hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((S or R)-(4-fluorophenyl)(4-methoxyphenyl)methyl)hexahydropyridine-1-carbonyl)hexahydro-2H- Pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((S or R)-(3,4-dimethoxyphenyl)(4-fluorophenyl)methyl)hexahydropyridine-1-carbonyl)hexahydro -2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((R or S)-(4-fluorophenyl)(4-methoxyphenyl)methyl)hexahydropyridine-1-carbonyl)hexahydro-2H- Pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(4-((S or R)-(4-(2-fluoroethoxy)phenyl)(4-fluorophenyl)methyl)hexahydropyridine-1-carbonyl) Hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-[3-[4-(trifluoromethoxy)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyridine And [4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-(3-(2'-trifluoromethoxy)-[1,1'-biphenyl]-4-yl)azetidine-1-carbonyl)hexahydro-2H -Pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(2'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)azetidine-1-carbonyl)hexahydro-2H -Pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(2',4'-difluoro-[1,1'-biphenyl]-4-yl)azetidine-1-carbonyl)hexahydro-2H- Pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-(3-(trifluoromethyl)azetidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H- Pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-Bromo-3-chlorophenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4 ] Oxazin-3(4H)-one; (4aR,8aS)-6-[3-[4-(4-chloro-2-fluoro-phenyl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8, 8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(2-chloro-4-fluoro-phenyl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8, 8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-(3-(4-(3-((1,1,1-trifluoropropan-2-yl)oxy)azetidin-1-yl)phenyl)aza Cyclobutane-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-(T-butyl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1, 4] Oxazine-3(4H)-one; (4aR,8aS)-6-(3-(4-(trifluoromethyl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1, 4] Oxazine-3(4H)-one; (4aR,8aS)-6-(3-(4-(3-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)azetidin-1-yl) Phenyl) azetidine-1-carbonyl) hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-(1,1-difluoroethyl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido(4,3-b ][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-(3,3-dimethylpyrrolidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[ 4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-(3-(trifluoromethoxy)azetidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H -Pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(6-(2,4-dichlorophenyl)pyridin-3-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido(4, 3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-[3-[4-(2,2,2-trifluoroethoxy)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8 ,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[3-[(1S or 1R)-2,2,2-trifluoro-1-methyl-ethoxy]azetidin-1-yl ]Phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[3-[(1R or 1S)-2,2,2-trifluoro-1-methyl-ethoxy]azetidin-1-yl ]Phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-(3-(4-(2-(trifluoromethyl)pyrrolidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido [4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-(3-(trifluoromethyl)pyrrolidin-1-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido [4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-(3-(2,2,2-trifluoroethoxy)azetidin-1-yl)phenyl)azetidine-1- Carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(6-(2-(trifluoromethyl)pyrrolidin-1-yl)pyridin-3-yl)azetidine-1-carbonyl)hexahydro-2H -Pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-(pentafluoro-l6-thio)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b] [1,4]oxazine-3(4H)-one; (4aR,8aS)-6-(3-(2-fluoro-4-(trifluoromethoxy)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3- b][1,4]oxazine-3(4H)-one; (4aR,8aS)-6-[3-[4-(2,2,2-trifluoroethyl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8, 8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[1-(trifluoromethyl)cyclopropyl]phenyl]azetidine-1-carbonyl]-4,4a,5,7,8 ,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(6,6-difluoro-2-azaspiro[3.3]hept-2-yl)phenyl]azetidine-1-carbonyl]- 4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-(3-(5-(2,4-dichlorophenyl)pyridin-2-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido(4, 3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-((R or S)-2-(trifluoromethyl)pyrrolidin-1-yl)phenyl)azetidine-1-carbonyl)hexa Hydrogen-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-((S or R)-2-(trifluoromethyl)pyrrolidin-1-yl)phenyl)azetidine-1-carbonyl)hexa Hydrogen-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-((R or S)-3-(trifluoromethyl)pyrrolidin-1-yl)phenyl)azetidine-1-carbonyl)hexa Hydrogen-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-((S or R)-3-(trifluoromethyl)pyrrolidin-1-yl)phenyl)azetidine-1-carbonyl)hexa Hydrogen-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido(4,3- b][1,4]oxazine-3(4H)-one; (4aR,8aS)-6-(3-(3-methyl-4-(trifluoromethoxy)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido(4,3 -b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(3,5-difluoro-4-(trifluoromethoxy)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido(4 ,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(3-chloro-4-(trifluoromethoxy)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3- b][1,4]oxazine-3(4H)-one; (4aR,8aS)-6-((R or S)-3-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)pyrrolidin-1-carbonyl)hexahydro- 2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-((S or R)-3-(3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)pyrrolidin-1-carbonyl)hexahydro- 2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-(T-butyl)-3-methoxyphenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido(4,3 -b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-propylphenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazine -3(4H)-one; (4aR,8aS)-6-(3-(4-(trifluoromethoxy)-3-(trifluoromethyl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido [4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(5-(((R or S)-3-(trifluoromethyl)pyrrolidin-1-yl)pyridin-2-yl)azetidine-1- Carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(5-((S or R)-3-(trifluoromethyl)pyrrolidin-1-yl)pyridin-2-yl)azetidine-1- Carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-[3-[6-[3-(R or S)-(trifluoromethyl)pyrrolidin-1-yl]-3-pyridyl]azetidine-1- Carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[6-[3-(S or R)-(trifluoromethyl)pyrrolidin-1-yl]-3-pyridyl]azetidine-1- Carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-(4-tetrahydropyran-3-ylphenyl)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydro Pyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[2-methoxy-4-(2,2,2-trifluoroethyl)phenyl]azetidine-1-carbonyl]-4,4a, 5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; and (4aR,8aS)-6-(3-(4-(neopentyloxy)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1 ,4]oxazine-3(4H)-one. A method for producing a compound of formula (I) according to any one of claims 1 to 50, which comprises: causing 4a, 5, 6, 7, 8, 8a-hexahydro-4H-pyrido[4,3-b ][1,4]oxazin-3-one ( 1 )

Reaction with heterocyclic amine 2a in the presence of a base and a urea-forming reagent, wherein A, L, X, m, n and R ²⁰ to R ²³ are as defined in any one of claims 1 to 50,

To form the compound of formula (Ic). The compound of formula (Ic) according to any one of claims 1 to 3 is produced according to the method according to claim 51. A compound of formula (Ic) according to any one of claims 1 to 3, wherein the IC _{50 of the} compound of formula (I) against monoacylglycerol lipase is less than 10 µM. The compound of formula (Ic) according to any one of claims 1 to 3, which is used as a therapeutically active substance. A pharmaceutical composition comprising the compound of formula (Ic) according to any one of claims 1 to 50, 52 and 53 and a therapeutically inert carrier. The compound of formula (Ic) according to any one of claims 1 to 3 for use in the treatment or prevention of neurological inflammation, neurodegenerative diseases, pain, cancer and/or mental disorders in mammals. The compound of formula (Ic) according to any one of claims 1 to 3, which is used for the treatment or prevention of multiple sclerosis, Alzheimer's disease, Parkinson's disease in mammals, Amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety disorder, migraine, depression, hepatocellular carcinoma, colon cancer development, ovarian cancer, neuropathic pain, nerves induced by chemotherapy Lesions, acute pain, chronic pain, and/or spasms associated with pain. Use of a compound of formula (Ic) according to any one of claims 1 to 50, 52, and 53 or a pharmaceutical composition according to claim 55 for the preparation or treatment of neuroinflammation and neurodegeneration in mammals Agents for sexual diseases, pain, cancer and/or mental disorders. Use of a compound of formula (Ic) according to any one of claims 1 to 50, 52 and 53 or a pharmaceutical composition according to claim 55 for the preparation of a medicament for the treatment or prevention of the following disorders in mammals: Multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety disorder, migraine, depression, hepatocellular carcinoma, Colon cancer development, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, acute pain, chronic pain, and/or pain-related spasm.